Therapeutic Range of INR

Warfarin therapy is guided by the prothrombin time. Separate laboratories use thromboplastin from different manufacturers which results in variability of the pro-thrombin time. The International Normalized Ratio (INR) is the prothrombin time ratio that would be obtained if the WHO reference thromboplastin reagent was used to test the plasma. Laboratories convert their local prothrombin time ratios to INRs by using the ISI (International Sensitivity Index) by the formula INR PT RATIOISI. The...

Table 195 APLA therapy

Venous or arterial thrombosis warfarin with target INR 2.0-3.0 Warfarin-refractory cases enoxaparin 1 mg kg every 12 hours Pregnancy History of thrombosis enoxaparin 1 mg kg every 12 hours No thrombosis enoxaparin 40 mg day aspirin Complications Short term prednisone 60 mg day immunoglobulin or anti-D Long term danazol 200 mg po qid Hypoprothrombinemia prednisone 60 mg day Catastrophic APLA syndrome Plasma exchange Cyclophosphamide 1 gram meter squared IV every 28 days aggressive...

A

Abciximab 50, 52, 53, 141, 144, 180-182 Activated partial thromboplastin time (aPTT) 17-21, 24, 27, 28, 31, 46, 47, 54-57, 62-64, 66-69, 71, 73, 74, 99-101, 108, 109, 136, 138, 141-143, 150, 155-161, 164, 165, 176, 186, 187, 189, 191, 203, 209, 210 56, 188-190 Adenocarcinoma 61, 110, 158, 192 Adrenal insufficiency 117, 135, 136 Alcohol 50, 51, 85, 171, 172 Alpha antiplasmin deficiency 45, 56 Amegakaryocytic thrombocytopenia 50, 51, 77 Aminocaproic acid 33, 67, 91, 92, 97 Amyloid 58, 186,...

Cancer and Thrombosis

Thrombosis As a Paraneoplastic Syndrome Thrombosis can be the presenting sign of cancer. As many as 10-20 of older patients who present with a deep venous thrombosis will be found to have cancer on initial evaluation. Furthermore, over the next two years as many of 25 of patients will develop cancer. Certain signs are more worrisome for cancer as an underlying cause of the thrombosis. Patients with warfarin-refractory thrombosis, idiopathic bilateral deep vein thrombosis, or both arterial and...

E

Ecarin time 23, 74, 161, 164 Ehrlichia 52, 87 Embolectomy 108, 152 Enoxaparin 71, 108-110, 113-115, 129, 137, 140, 141, 143, 156, 159, 166, 176, 202-204, 210 Eptifibatide 140, 141, 181, 182 Erythroid colony assay 124, 193 Erythropoietin 11, 54, 69, 193 Euglobulin clot lysis time 28, 45, Factor V deficiency 46, 56, 57 Factor V leiden 29, 111, 121, 123-126, 144, 152, 200, 201 Factor VII deficiency 17, 18, 27, 47, 55, 57, 67, 93 Factor VIII 2, 5, 6, 12, 19-21, 27-33, 35-41, 46, 47, 57-59, 65, 69,...

Pathogenesis

DIC is the clinical manifestation of inappropriate thrombin (IIa) activation (Table 8.1). Inappropriate thrombin activation can be due to causes such as sepsis, obstetric disasters and others. The activation of thrombin leads to 1) conversion of fi-brinogen to fibrin, 2) activation of platelets (and their consumption), 3) activation of factors V and VIII , 4) activation of protein C (and degradation of factors Va and VIIIa), 5) activation of endothelial cells, and 6) activation of fibrinolysis....

Therapy of Thrombosis in Myeloproliferative Syndromes

Intravenous heparin followed by warfarin is indicated for most patients with acute venous thromboembolism complicating the myeloproliferative disorders. Catheter-based thrombolytic therapy should be considered in patients who have acute occlusion of the hepatic or portal veins. Long-term oral anticoagulants (INR 2-3) are usually recommended for prevention of recurrent thromboses. In a few instances, liver transplantation has been successful in treating liver failure due to Budd-Chiari syndrome....

Warfarin

Warfarin works by interfering with vitamin K-dependent gamma-carboxylation of coagulation proteins II, VII, IX, and X. As a result ofwarfarin therapy, these coagulation factors cannot bind calcium. This causes impairment of these factors' binding to membranes and to fold into proper configuration. Therapy with warfarin is initiated by giving the patient 5-10 mg in the evening for the first two nights (2.5 mg in those over 75 years) and adjusting the dose to achieve an adequate prothrombin time....

R

Recombinant Vila 36, 47, 58, 93 Renal vein thrombosis 118, 208 Reptilase time 22, 28, 63, 191 Reteplase 141-143, 184, 185 Retinal vein thrombosis 119, 135 Rheumatic valve disease 146 Right atrial thrombosis 207 Ristocetin 39, 40, 44, 45, 59 Russell viper venom 24, 25, 124, 137 S deficiency 64, 123-126, 173, 209 Secretion defect 44 Sneddon's syndrome 134, 135 Splenectomy 52, 58, 62, 65, 76-81, 87, 118, 130, 191, 198, 199 Splenomegaly 50, 51, 58, 76, 80 Streptokinase (SK) 141-143, 184-186, 211...

Table 291 Pediatric dosing of heparin and LMWH heparin

< 1 year 28 units kg hr > 1 year 20 units kg hr Adjust to aPTT range that reflects heparin level of 0.35-0.70 anti-Xa units Enoxaparin < 5 kg 1.5 mg kg every 12 hours > 5 kg 1.0 mg kg every 12 hours attendant heparin exposure, HIT is common especially in children with cardiac disease. As with adult patients, LMWH offers several advantages in children, especially in ease of dosing and monitoring. Very small children (under 5 kg and or under two months of age) have higher dosage...

Managing Massive Transfusions

The approach to massive transfusions is to measure five laboratory tests which will reflect the basic parameters essential for both blood volume and hemostasis (Table 14.4). The tests are 4. Activated partial thromboplastin time Replacement therapy is based on the results of these laboratories with these guidelines (Table 14.5) For a platelets count less than 50-75,000 L, a plateletpheresis concentrate or 6-8 pack of single-donor platelet concentrate is given to the patient. Since the platelets...

Ticlopidine

Ticlopidine, a drug derived from thienopyridine, inhibits platelet aggregation at the newly discovered platelet receptor P2Y12. The antiplatelet effect appears to depend on a metabolite of the drug binding to the receptor. Functionally, ticlopidine appears to inhibit ADP-induced GP IIb IIIa activation. The dose is 250 mg orally twice per day. It may takes up to seven days to achieve full antiplatelet effect, but this does lasts the life of the platelet. Ticlopidine has been shown to be...

Table 112 Therapeutic options in splenectomy failures

Rituximab 375 mg m2 wk x 4 weeks Cyclophosphamide 1 gram m2 repeated every 28 days Danazol 200 mg qid + - azathioprine Dexamethasone 40 mg day x 4 days repeated every 28 days for six months Azathioprine 150 mg po daily, like danazol, demonstrates a delayed response and requires several months to assess for response. Recently it has been reported that the related agent mycophenalate 1000 mg bid is also effective in ITP. Cyclophosphamide 1 gm m2 IV repeated every 28 days has been reported to...

Decreased Production

So-called acquired amegakaryocytic thrombocytopenia is relatively rare. Most marrow disorders that lead to thrombocytopenia will cause other cell lines to be affected. The leading cause of isolated thrombocytopenia due to marrow problems is heavy (more than one fifth day) use of alcohol that leads to a megakaryocytic maturation defect. Clinically the platelets are small (MPV low). The count remains depressed for 3-5 days after alcohol is stopped but then rapidly rises with a rebound...

Suggested Reading

Acquired hemophilia. Rev Clin Exp Hematol 2001 5(4) 389-404. 2. Greinacher A, Eichler P, Lubenow N et al. Drug-induced and drug-dependent immune thrombocytopenias. Rev Clin Exp Hematol 2001 5(3) 166-200. 3. Crowther MA, Douketis JD, Schnurr T et al. Oral vitamin K lowers the international normalized ratio more rapidly than subcutaneous vitamin K in the treatment of warfarin-associated coagulopathy. A randomized, controlled trial. Ann Intern Med 2002 137(4) 251-4. 4. Michiels...

Table 111 Acute therapy of ITP

Prednisone 1 mg kg taper when count is over is 50,000 L over the course of four weeks For bleeding patients or counts below 5-10,000 L Immune globulin 1 gram kg iv repeat in 24 hours or Anti-D (WinRho) 75 g kg once Refractory patients Immune globulin 1 gram KG IV plus Anti-D 75 g kg plus Methyprednisolone 30 mg kg plus Vincristine 1.3 mg m2 (capped at 2mg) or Immune globulin 1 gram kg continuous infusion over 24 hours and Continuous infusion platelets (one plateletpheresis unit 6 hours or one...

Table 93 Therapy of coagulation defects associated with bleeding in liver disease

Protime > INR 2.0 and aPTT abnormal FFP. Platelets < 50-75k platelet concentrates. Fibrinogen < 125 mg dl 10 units of cryoprecipitate. Hematocrit < 30 packed red cells. L and the fibrinogen greater than 125 mg dl is more important than correction of the protime. Abnormal fibrinolysis is an often overlooked cause of bleeding in patients with liver disease. Bleeding in these patients tends to be characterized by diffuse oozing from minor trauma. Often these patients are futilely treated...

Recombinant Vila rVIIa

Although initially developed for use in hemophilia patients with inhibitors, there are more and more reports of the use of rVIIa for complex bleeding diatheses (Table 13.2). Clinical settings include trauma patients, patients with liver disease, patients bleeding while being anticoagulated with novel anticoagulants such as hirudin, and warfarin overdoses. Much of this data exists in case series and isolated reports. Exact Table 13.2. Current uses of rVIIa (NovoSeven) Table 13.2. Current uses of...

Table 72 Initial approach to thrombocytopenia

Obtain detailed history especially any and all drug exposure 2. Assess for lymphadenopathy and hepatosplenomegaly 4. Check liver function and renal function Examination of the blood smear can quickly reveal whether pseudo-thrombo-cytopenia is present and verify the degree of thrombocytopenia. The smear should be carefully reviewed for presence of schistocytes. An evaluation for DIC should be performed. Laboratory assessment of liver and renal function should also be reviewed. A markedly...

Budd Chiari Syndrome

Patients with Budd-Chiari syndrome or hepatic vein thrombosis present with the onset of a painful swollen liver and ascites and may progress to liver failure. Several hypercoagulable states are associated with Budd-Chiari syndrome (Table 16.1). These are myeloproliferative syndromes, antiphospholipid antibodies, paroxysmal nocturnal hemoglobinuria, and Befhet's disease. Budd-Chiari may be the presenting sign of a myeloproliferative syndrome and can occur with normal blood counts. This...

Clopidogrel

Clopidogrel is also a thienopyridine that inhibits platelet ADP receptors. It is dosed as 75 mg orally once per day a loading dose of 300-750 mg is being studied and seems to be effective in inducing a more rapid onset of antiplatelet action. Like ticlopidine, the antiplatelet effects can last for five days after cessation of therapy. In the CAPRIE trial, which has been the largest trial of clopidogrel to date, clopidogrel was slightly better than aspirin in the prevention of myocardial...

Antithrombotic Use of Pentasaccharides

One pentasaccharide, fondaparinux, is approved for use in DVT prevention with hip and knee replacement. The agent is renally cleared and should not be used in patients with renal insufficiency. Also, given the fixed dose (2.5 mg), it should not be used in patients weighing under 50 kilograms. Studies for DVT PE therapy have been performed using the dose of 7.5 mg daily (5.0 mg in patients under 50 kg and 10 mg in patients over 100 kg). The relative effectiveness of this agent vs LMWH is still...

Diagnostic Tests for Pulmonary Embolism and Deep Venous Thrombosis

Clinical Signs and Symptoms Patients first notice dyspnea and cough following a pulmonary embolism. Chest pain occurs hours to days after the event with development of lung infarction. One-third of patients will have hemoptysis, and 10-20 will have syncope. Most patients on exam will have tachypnea (70-92 ) but less then half have tachycardia (30 of patients in the classic PIOPED study). Chest x-rays are normal in only 30 . A nonspecific infiltrate is seen in 50-70 , and an effusion in 35 . In...

Surgery

Patients with ITP who need surgery either for splenectomy or for other reasons should have their platelet counts raised to a level above 20 - 30,000 L before surgery. Most patients with ITP have augmented platelet function and will not have excessive bleeding with these platelet counts. For patients with platelet counts below this level, an infusion of immune globulin or anti-D may rapidly increase the platelet counts. If platelet transfusion is required, the platelets should be leukoreduced to...

Table 202 Acute myocardial infarction Indications for warfarin anticoagulation therapy

History of systemic or pulmonary embolism. Mural thrombus on echocardiography. Atrial fibrillation (indefinite warfarin therapy). Anterior Q-wave infarction. Therapeutic heparin is recommended for at least 2-4 hours after simple procedures and for up to 24 hours in complicated patients. Aspirin 325 mg should be given before the procedure and should be continued indefinitely at a dose of 75 mg - 325 mg day. Abciximab therapy has been shown to be beneficial in all groups of patients undergoing...

Prevention of Embolism

Atrial fibrillation is the most common cardiac condition leading to embolism. The risk of stroke due to embolism in patients with atrial fibrillation is 3-7 year. As will be discussed below, several groups of patients have been identified as being at higher risk for embolism. Recently eight well-designed studies have clarified the role of anticoagulant therapy. These studies examined stroke prevention in patients with nonvalvular atrial fibrillation. The warfarin trials have established the...

Pathogenesis and Epidemiology

ITP is due to antibodies binding to platelet proteins, most often to the platelet receptor GP IIb IIIa. These antibody-coated platelets then bind to Fc receptors in macrophages and are ingested. The initiating event in ITP is unknown. It is speculated that the host responds to a viral or bacterial infection by creating antibodies which cross-react with the platelet receptors. Continued exposure to platelets perpetuates the immune response. ITP that occurs in childhood appears to be an acute...

Table 124 Options to consider for refractory patients

Twice daily 1 plasma volume plasma exchange Vincristine 1.4 mg m2 day 1 and then 1 mg days 4, 7, and 10 Rituximab 375 mg m2 weekly x 4 therapy for refractory TTP Patients who worsen while being treated are fortunately rare but present difficult challenges. In a patient with TTP who is worsening one should ensure the patient does not have another syndrome such as vasculitis or an Ehrlichia infection. These processes may present with a microangiopathy and multisystem failure. One maneuver which...

Pregnancy Related Thrombotic Microangiopathies

TTP can occur anytime during pregnancy. Diagnostic confusion is often present due to the overlap of TTP and HELLP syndrome. A unique presentation of TTP may occur in the second trimester at 20-22 weeks. The fetus is uninvolved with no evidence of infarction or thrombocytopenia if the mother survives. The pregnancy somehow promotes TTP since the TTP will resolve with termination and can recur with the next pregnancy. Therapy is either termination of pregnancy or attempting to support the patient...

The Congenital Hypercoagulable States Table 172

Factor V leiden (hereditary resistance to activated protein C HRAPC ) is a defect in factor V which renders it unable to be degraded by activated protein C. Factor V Leiden is associated with venous thrombosis. This mutation is very common it comprises 40 - 60 of hypercoagulable states, 20 of first DVTs, and is found in 2 - 8 of the normal population. It is estimated that the presence of factor V Leiden is associated with an increased relative risk of thrombosis of 3 fold. Prothrombin gene...

Vitamin KDeficiency

Vitamin K is critical in the synthesis of coagulation factors II, VI, IX, X, protein C, protein S and protein Z. Patients obtain vitamin K from food sources and from metabolism of intestinal flora. Vitamin K is used as a cofactor in gammacarboxylation of the vitamin K-dependent proteins. The gammacarboxylation involves oxidation of vitamin K. Vitamin K is recycled in a step blocked by warfarin. Despite being a fat soluble vitamin, body stores of vitamin K are low and the daily requirement is 1...

Deep Venous Thrombosis and Pulmonary Embolism

Venous thrombosis is unusual in children the vast majority of cases are secondary to other disease processes such as nephrotic syndrome. Inherited hypercoagu-lable states do not appear to play the major role in provoking pediatric venous thrombosis but may increase risk in synergy with acquired risk factors. Although pediatric studies are lacking, the use of doppler ultrasound remains the first choice for diagnostic tests. There is no data regarding the utility of D-dimers in the pediat-ric...

Special Situations

Heparin-induced thrombocytopenia (HIT) is common in patients being considered for cardiac surgery. Since anticoagulation is necessary to undergo bypass, the presence of HIT can be a challenge. One strategy is to wait until the titer of the HIT antibody has decreased enough to be undetectable. This clearance of the HIT antibody may take a few weeks. When the platelet aggregation assay or serotonin release assay is negative, the patient can be re-exposed to heparin for a few hours. This window of...

Table 221 Standard heparin vs low molecular weight heparin

Binds non-specifically to plasma proteins Increased plasma half-life with increased dose of drug Binds platelet factor 4 In therapeutic use must follow aPTT aPTT used to monitor Neutralized by protamine Short half-life Lacks non-specific binding Stable plasma half-life Most patients can be treated without levels

Acute Stroke

The patient with acute neurological defects demands a rapid decision as to whether the defect is ischemic in nature and, if so, what therapy should be instituted (Table 21.1). Patients with symptoms less than three hours old are candidates for throm-bolytic therapy. Evaluation of these patients should be rapid. Patients should undergo a CT scan to rule out hemorrhage or mass lesion. Evaluation for an underlying systemic process should also be undertaken. Patients who meet rigorous NINDS trial...

Correction of Warfarin Overdose Table 245

The key in approaching the patient with an elevated INR is to first determine if they are bleeding. Patients who are bleeding and have an elevated INR need an aggressive approach to reversal of their warfarin, while those just with an elevated INR can be managed less aggressively with the goal of allowing the INR to return to therapeutic range. However, the risk of bleeding in patients with an elevated INR may be substantial. A recent study showed that older patients being started on...

Table 213 Evaluation of the young patient with stroke

Antiphospholipid antibodies Lipoprotein (a) Plasma homocysteine Transesophageal echocardiogram Management of patients who have an embolic source of stroke and abnormalities on echocardiography is still controversial. The rate of recurrent stroke in patients with patent foreman ovale is approximately 1-2 per year. Therapeutic options include surgical correction or life-long anticoagulation. Patients with large defects, more than one event, or posterior circulation events appear to be at higher...

Preface

This handbook is designed to be a resource for both the common and uncommon hemostatic problems that health care providers often face in clinical practice. The handbook was written to offer a practical guide to recognizing, diagnosing, and managing these patients. Since the first edition many changes have occurred in hemostasis and thrombosis which require a new edition. One of the most remarkable areas of medicine continues to be the revolution in management thrombotic diseases. This includes...

Clinical Presentation Table

Patients can present in one of four ways with DIC. 1. Asymptomatic. Patients can present with laboratory evidence of DIC but no clinical problems. This is often seen in sepsis and in cancer. However, with further progression of the underlying disease, these patients may rapidly become symptomatic. 2. Bleeding. Most patients with DIC bleed. The bleeding is due to a combination of factor depletion, platelet dysfunction, thrombocytopenia, and excessive fibrinolysis. These patients may present with...

Description Table 141

One platelet concentrate (one unit of random donor platelets) is derived from one unit of donor blood. Single-donor plateletpheresis can be used to harvest platelets. One unit of single donor (pheresis) platelets is equivalent to 6-8 platelet concentrates. Single-donor platelets offer the advantage of exposure to only one blood donor. One platelet concentrate can raise the platelet count by 5-7,000 L. Platelets are mildly stunned while in storage and it takes four hours for transfused platelets...

Antithrombotic Use of Low Molecular Wfeight Heparin

These are derivatives of heparin with improved anti-Xa effect and less antiplatelet effect (Table 22.1). Several trials have shown that the LMW heparins have an improved risk-benefit ratio over regular heparin. Since LMW heparin does not bind to acute phase proteins or endothelial cells, its pharmacokinetics are more predictable than that of standard heparin. For prophylactic use, LMW heparins can be administered once or twice daily without the need for laboratory monitoring. There is now...

Bleeding Disorders A General Approach

Patients with bleeding disorders may present in a variety of ways. Using the history and basic screening tests, one can narrow the differential considerably. Key questions to ask are (Table 3.1) Patient perception of bleeding is not always useful in diagnosing a bleeding disorder. One should specify in detail the history of bleeding. The following questions are helpful in obtaining a bleeding history 1. Have you ever had a nosebleed How frequently do these occur Has any required a trip to the...

Table 145 Management of massive transfusions

Assess need for empiric platelet or cryoprecipitate transfusion. 3. Assess need for products based on results of basic five tests A. Platelets < 50-75,000 L give platelet concentrates or 6-8 pack of single donor platelets. B. Fibrinogen < 125 mg dl give 10 units of cryoprecipitate. C. Hematocrit below 30 give red cells. D. Protime > INR 2.0 and aPTT abnormal give 2-4 units of FFP. For a fibrinogen level less than 125 mg dl, 10 units of cryoprecipitate...

O

81, 117, 118, 122, 129, 195 Peripheral vascular disease 130, 134, 152, 153, 178 Plasma exchange 86-90, 97, 137, 199, 200 Plasma infusion 45, 64, 86, 87, 136 Plasmapheresis 36, 53, 64, 88, 136, 137, 191 (PAI-1) 2, 10, 28, 45, 56, 184, 185, 196 Platelet activation 12-14, 84, 85, 159, 180 Platelet alloimmunization 43, 80, 96, Platelet defect 27, 43, 54, 73, 190 Platelet function 1, 20, 28, 43-45, 53, 54, 66, 68, 72, 73, 79, 84, 93, 112, 177, 180, 182, 190, 191 Platelet neutralization test 24...

Practical Approach to the Refractory Patient

One approach is to divide patients into bleeders and nonbleeders. Bleeders have either very low platelet counts (under 5,000 L) or have had significant bleeding in the past. Non-bleeders have platelet counts above 5,000 L and no history of severe bleeding. Bleeders who fail splenectomy should receive aggressive therapy with immuno-suppression. One approach to is first start with rituximab since it is not cytotoxic. If rituximab does not work then one can consider bolus cyclophosphamide. If this...

Rat Poison

Warfarin used to be the rodenticide in commercially available rat poisons. Certain rats (by anecdote from New York City) became resistant to warfarin. Now rat poison contains brodifacoum as the main rodenticide. Brodifacoum binds and irreversibly inhibits vitamin K recycling. Furthermore, it is highly fat soluble and has a long half-life. Patients who ingest rat poison present with an elevated PT-INR that is only transiently responsive to fresh frozen plasma or to small doses of vitamin K....

Agents

Streptokinase was the first thrombolytic agent. It is derived from Streptococcus. Streptokinase has a long half-life. Streptokinase first cleaves plasminogen by a cumbersome mechanism wherein streptokinase first binds to plasminogen. This complex then cleaves a new molecule of plasminogen to form plasmin. One unique side-effect is that patients can develop antibodies to streptokinase due to prior use or due to a recent Streptococcal infection. tPA was one of the first drugs manufactured by...

Peripheral Vascular Disease

Patients who present with an acute occlusion of the arterial blood supply of a limb require rapid intervention to save the limb. The time window is only four to six hours from onset of ischemia for limb salvage. Patient may suffer either an embolism or sudden thrombosis of a pre-existent atherosclerotic area. Patients with em-bolic disease often just require removal of the thrombus. Patients with thrombosis over atherosclerosis often require re-vascularization therefore, differentiating between...

Estimated Fetal Radiation Exposure

Fetal exposure to radiation is a significant concern when evaluating the pregnant patient for venous thrombosis pulmonary embolism (Table 28.3). Exposure of the fetus to less than 5,000 mrads is not teratogenic (threshold is in the range of 25,000 mrads). Threshold for oncogenicity is more controversial without definite studies. Review of the pertinent literature reveals it is likely that fetal exposure to small amounts (< 5,000 mrads) may be associated with a relative risk of leukemogenesis...

Classification

Since the underlying pathophysiology and etiology of many of the TMs are unknown, any classification scheme is imprecise (Table 12.1). In addition, many of the signs and symptoms of TM overlap, especially thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS). However, several classic syndromes do stand out. TTP and HUS are the opposite ends of a spectrum of disease involving TM, renal disease, and multi-organ system involvement. Pregnancy is associated with a unique TM,...

Factor Xiii Fibrin Clot

Formation of the fibrin clot. Fig. 1.11. Formation of the fibrin thrombus. Thrombin acts on fibrinogen to cleave fi-brinopeptide A and B. This forms the fibrin monomer that loosely polymerizes. Factor XIII covalently bonds the fibrin monomer to form a stable thrombus. Fig. 1.11. Formation of the fibrin thrombus. Thrombin acts on fibrinogen to cleave fi-brinopeptide A and B. This forms the fibrin monomer that loosely polymerizes. Factor XIII covalently bonds the fibrin monomer to form...

Approach to the Patient Suspected of Having a Hypercoagulable State

Unfortunately (unlike with bleeding disorders) no screening tests for hyperco-agulable states are available. The clinical setting should guide ordering a rational evaluation. When evaluating a patient one should ask the following questions Is the Thrombosis Arterial or Venous A critical piece in planning the evaluation is determining whether the thrombosis is arterial or venous. Most hypercoagulable states manifest themselves as predominantly venous thrombosis. Although anecdotal reports of...

Table 224 Heparin induced thrombocytopenia scoring system

Onset day 5-10 of heparin or < 1 day if patient recently exposed to heparin New thrombosis or skin necrosis or systemic reaction with heparin No 30-50 fall or nadir Fall < 30 or 10-19,000 ul nadir < 10,000 ul consistent but not clear records or count falls after day 10 Progressive or recurrent thrombosis or suspected but not proven thrombosis Possible platelets falls < 5 days and no recent (100 days) heparin Pretest Score 6-8 high, 4-5 intermediate, 0-3 low Warkentin, Heddle Current...

Management of the Platelet Refractory Patient

Patients who are refractory to platelet transfusion present a difficult clinical problem (Table 14.2). If patients are demonstrated to have HLA antibodies, one can transfuse HLA-matched platelets. Unfortunately, platelet transfusions do not work in 20 - 70 of these patients. HLA-matched platelets are matched for anywhere from 1 - 4 HLA loci. Some loci are difficult to match so good matches may be unavailable. As many as 25 of patients have anti-platelet antibodies in which HLA-matched products...

Ranges of Normal

The levels of many coagulation proteins are different in pediatric populations. Most coagulation protein levels are low at birth and slowly rise to adult range over the first year of life. However, levels of vitamin K-dependent proteins don't completely rise to the adult range until the teenage years of life. Levels of antithrombin and proteins C and S are significantly lower at birth with protein C levels remaining lower than adult range until the teenage years. It is important when...

Immediate Therapy

Venous Thromboembolism

Thrombolytic therapy Given the natural history of pulmonary embolism, the role of thrombolytic therapy is uncertain. That thrombolytic therapy lyses clots Fig. 15.2. Diagnostic flowchart for pulmonary embolism using point of care D-dimer. Fig. 15.2. Diagnostic flowchart for pulmonary embolism using point of care D-dimer. faster then heparin was of no clinical significance in the large trials of the early 1980s or in more recent trials. For example, 24-hour lung perfusion improved by 2.7 in a...

Table 162 Priapism

High Flow Increased arterial blood flow to penis Low Flow Obstruction of venous drainage Sickle cell disease DIC with thrombosis Venous trauma Tumor infiltration Medications Diagnostic Approach Aspiration of corporeal blood for blood gas analysis pH less than 7.25 and oxygen less than 30 mmHg suggestive of low flow state Treatment of Low-Flow Priapism Corporeal aspiration of 60 ml of blood and injection of 200 g of phenylephrine Repeat for a Total of Three Injections (if needed) If this fails...

Acquired von Willebrand Disease

Acquired von Willebrand disease (vWD) has been reported to occur in lymphomas, myeloproliferative syndromes, myeloma, monoclonal gammopathies and with the use of certain drugs. Acquired deficiency of von Willebrand proteins (vWF) can occur by several mechanisms. One is by protein absorption to the surface of the malignant cell. Malignant cells in lymphomas, myelomas and Wilms tumors can express GP Ib. Another mechanism is by antibody binding to the protein. The most common drug-induced etiology...

Paroxysmal Nocturnal Hemoglobinuria PNH

PNH is a rare hematological disorder that most often presents with low blood counts, hypocellular bone marrow and a high incidence of thrombosis. The underlying problem is a mutation in a gene which encodes a protein linking membrane proteins with the phospholipid membrane. The loss of these proteins causes a variety of clinical effects. The disease takes it name from the loss of red cell membrane proteins which inactivate complement, rendering erythrocytes more susceptible to lysis. With the...

Approach to the Bleeding Bypass Patient Table 103

If the patient is still in the operating suite and starts to have microvascular bleeding, one should check a full panel of coagulation testing including the platelet counts, PT-INR, PTT and fibrinogen. Patients who have had multiple transfusions of cell-saver blood or of packed red cells may have dilutional coagulation defects that need to be replaced with heparin and cryoprecipitate. In the bleeding patient still on bypass, an infusion of desmopressin is indicated. Given a platelet defect, if...

Air Travel

Recently much attention has been given to thrombosis due to airplane travel. Case-control studies suggest a relative risk of thrombosis of 3-4 fold with prolonged (over four hours) travel with a high risk for longer travel times. It is uncertain what the absolute risk for thrombosis is. The overall risk of symptomatic pulmonary embolism is estimated to be 0.4 per million passengers rising to 4 per million in the highest risk group. In contrast, a small prospective trial showed a calf vein...

Special Issues

Women with Antiphospholipid Antibodies (APLA) Women with APLA and thrombosis should be aggressively anticoagulated during pregnancy. However, the management of women with APLA without thrombosis is extremely controversial. The use of heparin plus low-dose aspirin has been shown to be more effective than aspirin alone in patients with APLA. It is not known whether the aspirin is really necessary but until this is studied, combination therapy should be used. Women with persistent high-titer APLA...

Acute Myocardial Infarction Acute Therapy

The patient who presents with chest pain needs to be rapidly evaluated for myo-cardial ischemia. Patients with evolving myocardial infarctions require rapid therapy to re-open the occluded coronary artery. Currently patients may be either treated with thrombolytic therapy or may undergo immediate coronary angioplasty. Data does suggest that if PCI can be performed within 3-6 hours, it is preferable to thrombolytic therapy. All patients with AMI, no matter what the definitive therapy will be,...

Behets Disease

Thrombosis is a frequent finding in patients with Befhet's. Patients may have both arterial and venous thrombosis. Patients with Befhet's have a predilection for both Budd-Chiari syndrome and cerebral vein thrombosis. Pathogenesis is probably a combination of the underlying inflammatory disease and vasculitis. The arterial thrombosis is either at the site of vasculitis or due to aneurysm formation. Case reports have shown co-existing antiphospholipid antibodies in some patients with Befhet's....

Table 81 Consequences of excessive thrombin generation

Conversion of fibrinogen to fibrin thrombosis and depletion of fibrinogen 2. Activation of platelets thrombocytopenia 3. Activation of factors V, VIII, XI, XIII thrombosis and depletion of coagulation factors 4. Activation of protein C depletion of factors V and VIII and eventually protein C 5. Activation of endothelial cells expression of tissue factor 6. Activation of fibrinolysis lysis of thrombi and depletion of fibrinogen 6. Activation of fibrinolysis leads to breakdown of fibrin monomers,...

Table 283 Estimated fetal exposure

Bilateral venography w o abdomen shield Unilateral venography w o abdomen shield V Q scans are sensitive but not specific. V Q scans are best viewed as high probability,negative and non-diagnostic. One can minimize the radiation exposure by performing the perfusion scan first. If this is normal then there is no need to perform a ventilation scan. CT scans are now the most popular method of diagnosing PE. Although specific, CT scans are only about 70-80-- sensitive and by themselves are not...

Relapsing TTP

Between 30-60 of patients successfully treated for TTP may relapse. Relapse can either be early (less than 30 days after stopping plasma exchange) or late. Early relapses are often due to inadequate therapy and can be severe. Late relapses can range in severity. Some patients will present early on with subtle signs while others will present with seizures. Relapsing patients typically respond to standard TTP therapy. In patients with early relapse, one should continue therapy until there is...

Antibiotics

Antibiotics can affect vitamin K metabolism in two ways. Most antibiotics with activity against anaerobes can sterilize the gut, eliminating microbial production of vitamin K. Certain cephalosporins that contain the N-methylthiotetrazole (NMTT) group can inhibit vitamin K epoxide reductase. This prevents the normal recycling of vitamin K. The most commonly implicated antibiotics are cefamandole, cefoperazone, cefotetan, cefmenoxime and cefmetazole. NMTT is released from the antibiotic and...

Treatment of Deep Venous Thrombosis

There is now abundant evidence that use of low molecular weight heparin (LMWH) for therapy in DVT PE treatment is both safer and more effective than use of standard heparin. Evidence is also clear that stable patients with DVT PE can be treated at home with LMW heparin. There are two low molecular weight hep-arins (LMW heparin) approved for therapy, enoxaparin 1mg kg every 12 hours or tinzaparin 175 units kg every day. For patients with low thrombotic burden one may use enoxaparin 1.5 mg kg...

Complications of Heparin

Approximately 5 of patients placed on therapeutic heparin will bleed. Some patients appear to be more at risk than others. Patients without risk factors for bleeding have a complication rate of 1 , whereas those with risk factors have rates of bleeding of 10-23 . Risk factors include use of aspirin, age greater than 60, liver disease, and other severe illness (cancer, heart disease). The risk of bleeding is small in patient receiving prophylactic heparin. Multiple double-blind trials have shown...

Adrenal Infarction

The adrenal gland contains a plexus of small veins and venules which receive the secreted hormones of the adrenal gland. This venous structure appears prone to thrombosis in several hypercoagulable states. Patients with purpura fulminans may present with adrenal crisis due to thrombosis and the resultant hemorrhagic destruction of the gland. Patients with heparin- induced thrombocytopenia may rarely infarct the gland and have subsequent hemorrhage. Finally, patients with antiphospholipid...

Clinical Presentation

Many patients with TTP will first have a prodrome of a flu-like or diarrheal illness. Patients can present with a variety of conditions ranging from general malaise to sudden death. The disease can strike at any age, although the predominant age is 20-40 years of age. Women are affected more than men in a 2 1 ratio. The classic reported pentad of fever, mental status changes, renal insufficiency, thrombocytopenia and microangiopathic hemolytic anemia is seen in less than 40 of patients (Table...

Table 244 Vitamin content of foods

Beef liver Spinach Watercress Asparagus Lettuce (iceberg) Green beans 712 634 408 317 220 200 192 129 125 125 92 89 57 57 26 14 The therapeutic INR range for most indications for warfarin is an INR of 2.0-3.0. Patients with mechanical heart valves will require higher doses of warfarin to aim for a target INR of 3-4.5. To avoid subtherapeutic doses of warfarin, it is better to aim for a target INR of 2.5 and use the range of 2-3 as indicating acceptable values. Use of the mid-range target as a...

Liver Transplantation

The advent of liver transplantation has significantly impacted the survival of patients with severe liver disease. Patients may require astonishing amounts of blood during the procedure. Totals of more than 100 units of red cells and plasma are not unusual in these patients. Before liver transplant is considered, baseline coagulations status should be determined. However, baseline coagulation defects are not predictive of bleeding with surgery. Certain operative features are more predictive of...

Bleeding Syndromes

The hemostatic defects in patients with APL are multiple. Most if not all patients with APL have evidence of DIC at the time of diagnosis. Patients with APL have a higher risk of death during induction therapy when compared with patients with other forms of leukemia. But, once is remission, APL patients have a higher cure rate than most patients with leukemia. APL is also unique among leukemias in that biological therapy with retinoic acid is effective in inducing remission. Patients can...

Retinal Vein Thrombosis

Retinal vein thrombosis is a not-uncommon cause of impaired vision. Despite the venous infarction, patients with retinal vein thrombosis do not appear to have a higher incidence of underlying hypercoagulable states. Instead, risk factors for arterial disease are often present. The retinal artery and vein share the same sheath in the eye and a rigid atherosclerotic artery may predispose to compression of the vein. Patients with branch retinal vein thrombosis also tend to have the artery...

Therapy Table 123

Mortality in the pre-plasma era ranged from 95 to 100 . Present day plasma exchange therapy is the cornerstone of TTP treatment and has reduced mortality to less than 20 . However, despite adequate therapy, patients often die either of refractory disease or suddenly during the early course of therapy. Steroids in doses of 60 mg day intravenously of prednisone are routinely given. This should be continued until the patient has fully recovered. Very mild cases of...

Semantics

APLA syndrome Patients with APLA and one major clinical criterion are said to have APLA syndrome. The major clinical criteria include venous or arterial thrombosis (including neurological disease such as stroke), thrombocytopenia, or frequent miscarriages. (Table 19.1) Secondary APLA syndrome is APLA plus another autoimmune disease, most commonly lupus. Primary APLA syndrome is APLA syndrome occurring outside of the setting of lupus. In distinction to SLE-APLA patients, primary APLA patients...

Atypical HUS

Atypical HUS is defined as a HUS syndrome which lacks the typical features. This description obviously lacks diagnostic precision. In general this term has been applied to HUS which has prominent extra-renal symptomatology. HUS in older patients and HUS without preceding diarrhea fit this category. The prognosis is thought to be worse for atypical HUS. Therapy for atypical HUS is plasma exchange. Patients with atypical HUS, especially older patients, may require months of plasma exchange...

Massive Transfusions

Massive transfusion is defined as giving more than one blood volume in 24 hours or less. It is more practically defined as giving one blood volume in two hours or less. Patients requiring massive transfusion will require close attention to detail and careful monitoring for complications. The complications that can be seen with massive transfusions are hyperkalemia, hypothermia and hypocalcemia. Hypothermia is the most common. Red cells are stored at 4 degrees Celsius and the infusion of red...

Acquired Coagulation Factor Deficiency

Acquired defects of hemostasis may first present with either prolongation of routine coagulation laboratory values or with a serious bleeding diathesis. Frequently DIC and liver disease present with both PT and aPTT elevated. If there is no evidence of either disorder then further testing is needed. A 50 50 mix that corrects establishes the presence of factor deficiency. One that does not correct (even with added phospholipids) suggests a specific factor inhibitor. The first step in evaluation...

Portal Vein Thrombosis

Portal vein thrombosis can occur either as a complication of local inflammation or be a sigh of hypercoagulable states. Local factors associated with portal vein thrombosis include abdominal abscess, inflammatory bowel disease, or tumor compression. Portal vein thrombosis can also be a complication of surgery, especially splenectomy in patients with myeloproliferative disorders. Like Budd-Chiari syndrome, portal vein thrombosis can also be a complication of hypercoagulable states including the...

Table 172 Inhertied hypercoagulable states

Factor V leiden Prothrombin gene mutation Protein C deficiency Protein S deficiency Antithrombin III deficiency Dysfibrinogenemia 2-8 1-2 1 200 1 2-5,000 1 2-5,000 Rare Protein S is a cofactor for Protein C. Protein S exists both in bound and unbound form. Deficiencies of total protein S and of unbound protein S (more common) can lead to a hypercoagulable state. Like protein C deficiency, the risk of thrombosis is increased ten fold, with the risk for carriers 0.9- 3.5 year. Protein S...

Inflammatory Bowel Disease

Patients with inflammatory bowel disease are at higher risk for thrombosis. Autopsy series show that 33 of patients had thrombi present. It appears that the presence of inherited hypercoagulable states also raises the risk of thrombosis in these patients. Patients with inflammatory bowel disease complicated by thrombosis usually present with deep venous thrombosis of the lower extremity. An increased risk of visceral vein thrombosis has also been reported, perhaps due to local inflammation....

Diagnosis

Extremely low platelet counts with a normal blood smear and a negative history is diagnostic of ITP. One should question the patient carefully about drug exposure (see drug-induced thrombocytopenia), especially about over-the-counter medicines, natural remedies or recreational drugs. There is no laboratory test that rules-in ITP rather, it is a diagnosis of exclusion. The blood smear should be carefully examined for evidence of microangiopathic hemolytic anemias (schistocytes), bone marrow...

Table 231 Argatroban hirudin and bivalirudin

Therapy 2 g kg min infusion with dose adjustments to keep aPTT 1.5 - 3 times normal. For patients with severe liver disease, start with 0.5 g kg min infusion and follow aPTT to same goal of aPTT 1.5 - 3 times normal. For PCI Bolus with 350 g kg over 3-5 minutes and then infuse with a maintenance drip of 25 g kg min adjusting to a ACT of 350-400 minutes. Hirudin Therapy bolus of 0.4 mg kg followed by 0.15 mg kg hour to maintain an aPTT of 1.5-3.0 times normal. Adjustments for Renal Dysfunction...

Antithrombotic Therapy for Peripheral Vascular Disease

The first-line of therapy for all patients is antiplatelet therapy with either aspirin or clopidogrel. Patients with peripheral vascular disease are at high risk for myocar-dial infarction and stroke in addition to their peripheral vascular diseases and these processes will also benefit from antiplatelet therapy. Data suggests that patients undergoing femoropopliteal bypass surgery using prosthetic grafts should be started on warfarin INR 1.4 - 2.8 and aspirin 81mg -325mg day pre-operatively.

Table 102 Coagulation defects associated with cardiopulmonary bypass surgery

Activation of tissue factor pathway Patients with severe pulmonary hypertension can develop acquired type 2A von Willebrand disease. This may be due to destruction of the high molecular weight multimers by the damaged pulmonary endothelium. The affected patients can also have marked thrombocytopenia. These patients can have a severe bleeding diathesis. Patients with pulmonary hypertension and bleeding should undergo a phlebotomy to lower the hematocrit to less...

Differential Diagnosis

Given the variety of non-specific symptoms associated with TTP, accurate diagnosis may be difficult. As mentioned, the classic pentad is present in only 40 of patients. Patients seen initially are often given a variety of diagnoses ranging from alcohol withdrawal to septic shock syndrome. Since TTP may be seen in patients with lupus, confusion exists between the two diagnoses. One report indicates that 24 of patients dying with lupus cerebritis had pathologic evidence of TTP. TTP should always...

Etiology

In essence, anything that leads to an overproduction of thrombin will cause DIC. This overproduction of thrombin can result from an immense number of clinical situations (Table 8.2). A few of the more common ones are listed below. Infection can lead to DIC via several pathways. Endotoxin produced by gram-negative bacteria results in expression of tissue factor by both endothe-lial cells and monocytes. Certain organisms such as Rickettsia and viruses of the herpes family can directly infect...

Heparin and Heparin Like Drugs

Heparin functions as an antithrombotic agent by binding antithrombin (AT), promoting inactivation of the active serine proteases involved in blood coagulation (factors IIa, VIIa-TF, IXa, Xa, and XIa). Heparin is a blend of saccharide polymers ranging in molecular weight from 3-30,000 daltons. A specific pentasaccharide sequence is required for promoting AT activity. This sequence is found in only one-third of the heparin molecules in the heparin currently used. Other polymers found in heparin...

Table 113 Differential diagnosis of Evans syndrome

Congenital hemolytic syndromes Paroxysmal nocturnal hemoglobinuria Thrombotic thrombocytopenic purpura Many patients with paroxysmal nocturnal hemoglobinuria will be thrombocytope-nia. In patients with liver disease both Wilsons disease and spur cell anemia are rare causes of severe hemolysis. In theory the diagnostic approach is straightforward by showing a Coombs positive hemolytic anemia in the setting of a clinical diagnosis of immune thrombocy-topenia. The blood smear will show...

Diagnostic Approach

If available, a negative rapid high sensitivity D-Dimer eliminates the need for further evaluation of patients suspected of having DVT. If the high-sensitivity assay is not available, then clinical probability of DVT should be assessed. If the clinical probability is not low, then doppler-ultrasound of the lower extremities is performed. If this is positive, the patient requires antithrombotic therapy. If it is negative and the patient had a low pre-test probability for...

Table 242 Maintenance warfarin adjustment nomogram Hatheway and Goodnight

Day 1 Add 10-20 total weekly dose (TWD)* Stop warfarin until INR < 3.0 Decrease TWD by 20-50 Return daily weekly to ensure the INR is stable. If the patient is started on a drug which results in predictable changes in the INR, then the warfarin dose may be adjusted, usually by 50 , when starting that drug. Vitamin K is found in many foods (Table 24.4), especially green vegetables. Patients will often avoid any vegetables due to fear of reversing their anticoagulation. This will result in...

Table 181 Renal transplants in hypercoagulable patients

Renal Transplant Patients at Risk for Graft Thrombosis 1. Previous AV fistula thrombosis 3. Presence of antiphospholipid antibodies 4. Previous large vein renal transplant thrombosis Protocol for Renal Transplant Patients at High Risk of Thrombosis 1. 2 hours before surgery, enoxaparin 20 mg subcutaneously 2. Start daily enoxaparin 20 mg subcutaneously 3. Start warfarin evening after surgery with goal INR 2-3 4. Continue warfarin for at least 6 weeks after transplant

Preparation for Surgery

Patients with liver disease often require surgical procedures. Pre-surgical laboratory screening should consist of the hematocrit, platelet count, PT-INR aPTT, fi-brinogen, D-dimer and euglobulin clot lysis time. Patients with compensated fibrinolysis may rapidly defibrinate during surgical procedures. Before surgery, the platelet count should be increased to over 50,000 L and the fibrinogen to over 100 mg dl. Plasma can be used to lower the PT-INR aPTT but often only a minimal reduction will...

Antiphospholipid Antibodies APLA

APLA are antibodies directed against certain phospholipids. They are found in a variety of clinical situations. APLA are important to detect because in certain patients they are associated with a syndrome which includes a hypercoagulable state, thrombocytopenia, fetal loss, dementia, strokes, optic changes, Addison's disease, and skin rashes. The underlying mechanism leading to the clinical syndrome associated with APLA is still unknown. Perhaps the antibodies inhibit the function of proteins C...

Symptoms

Patients first present with petechiae small bruises 1 mm in size on the shins. True petechiae are only seen in severe thrombocytopenia. Patients will also notice frequent bruising and bleeding from the gums. Patients with very low platelet counts will notice wet purpura blood-filled bullae in the oral cavity. Life-threatening bleeding is a very unusual presenting sign unless other problems (trauma, ulcers) are present. The physical examination is only remarkable for stigmata of bleeding such as...

Previous Deep Venous Thrombosis

These women are at high risk for recurrence and should receive prophylaxis. Most women with a history of thrombosis should receive prophylaxis for the duration of the pregnancy. Woman with a history of an non-estrogen related provoked DVT may only need prophylaxis for delivery and 6 weeks postpartum. An example of this would be a patient who suffered a DVT after a leg fracture. Most experience is with enoxaparin 40 mg every day or with dalteparin 5,000 -7,500 units every day. Warfarin is given...

Nephrotic Syndrome and Other Renal Disease

Nephrotic syndrome has long been associated with a hypercoagulable state. Patients with nephrotic syndrome have an increased incidence of renal vein and other thrombosis. Less well-known is that patients with renal failure in general have a higher incidence of thrombosis. Thrombosis of vascular grafts is one difficult problem. Occasional patients will suffer multiple graft thrombi which will impair their ability to undergo dialysis. Pathogenesis of the hypercoagulable state in nephrotic...