COMPLETE HOW TO TREAT QUIZZES ONLINE ( to earn CPD or PDP points.

Transcription

1 HowtoTreat PULL-OUT SECTION COMPLETE HOW TO TREAT QUIZZES ONLINE ( to earn CPD or PDP points. inside Diagnosing venous thromboembolic disease Investigations Management Pregnancy and thrombophilia Prevention of VTE Clotting The author conditions DR STEVE FLECKNOE-BROWN, consultant physician and clinical pathologist, Broken Hill, and senior lecturer, Sydney School of Public Health, University of Sydney, NSW. Background WE live in extraordinary times, not the least in how we are finding solutions to age-old medical issues. Progress in the understanding of, and therefore the manipulation of, the clotting process underpins many of the spectacular advances in cardiology, stroke management and, of course, prevention and management of venous thromboembolic disease (VTE). Aetiology and pathogenesis of venous thrombosis It is important to understand that the treatment of arterial thrombosis and the treatment of venous thrombosis are quite different, and that these treatments do not complement each other. Arterial thrombosis arises in what fluid physicists call high shear situations. The difference between the velocity of flow in the middle of an artery and that close to its wall is quite large. In high-shear flows, turbulence will activate platelets. For this reason treatments that weaken platelet function, such as aspirin, are central to preventing thrombosis in arteries affected by atheroma. Venous thrombosis occurs in lowshear flow conditions; the velocity of the blood flow in the centre of the vein is almost the same as that at the edge. Rudolf Virchow ( ), called the father of cellular pathology, is credited with defining the circumstances in which venous thrombosis occurs: Alterations in normal blood flow. Injuries to the vascular endothelium. Alterations in the constitution of blood. Chronic or intermittent atrial fibrillation, producing a left atrial thrombus, is also due to low-shear flow thrombosis. So, although this may result in arterial thromboembolism, management uses the same principles as for venous thrombosis. Successful treatment of VTE, and prevention of systemic embolism in atrial fibrillation, depend on systemic anticoagulation with heparin and/or warfarin. Aspirin has no place in treatment or prevention of VTE or management of AF. Most of us were taught that superficial thrombophlebitis is benign and does not lead to embolisation, so treatment should focus on local antiinflammatory measures. However, most vascular specialists and haematologists have seen the occasional lower-limb superficial thrombosis propagate into the deep veins. A group of French researchers have now reported that 25% of people they examined with superficial thrombophlebitis also had DVT or pulmonary embolism (PE) at presentation, and that a further 10% developed VTE within three months. 1 As this is the first such claim, it will need closer scrutiny and larger studies before it changes practice. cont d next page 21 May 2010 Australian Doctor 33

2 Physiological clotting Figure 1: A simplified scheme of the coagulation process and its relation to clot-limiting factors. (Image reproduced courtesy of John Griffin) BLOOD vessel injury, whether by complete section or by endothelial damage, sets in train a sequence of physical, cellular and chemical events that eventually result in sealing off the breach and, ultimately, to remodelling of the vessel. The first response to blood vessel injury is vascular smooth muscle spasm, which can temporarily arrest blood loss. Exposure of platelets to collagen and other substances in the vessel wall activates them. This turns them from slick discshaped particles to burr shapes, which fall out of the circulation and aggregate rapidly, forming a raft that plugs the hole in the vessel wall. Platelet activation, as well as exposure of the plasma to tissue factors, activate the plasma-clotting factors, which in turn lead to production of thrombin from prothrombin. Thrombin cleaves soluble fibrinogen, allowing the fragments to polymerise into longstranded fibrin. These long strands of fibrin sweep up passing red blood cells and more platelets, producing the soft clot that forms within minutes of the injury. Meanwhile, thrombin that has escaped into the circulation from the site of clotting activates other enzymes, among them protein C, its co-factor protein S and plasminogen (figure 1). Activated protein C is a serine protease enzyme that cleaves activated factors V and VII, inactivating them and preventing ongoing thrombosis beyond the site of the initial clot. Anti-thrombin III removes thrombin from the circulation. Plasmin, produced from plasminogen, digests fibrin, thus trimming the clot to the size needed. When fibrin is broken down by plasmin, it releases the D-dimer fragment into the circulation. Thus it can be seen that checks and balances are activated at the same time that the clotting process is started. Without them we would clot our entire system after minimal trauma. Indeed that is what happens in purpura fulminans, a condition that affects neonates born with homozygous protein C deficiency. Fibrinolysis with synthetic tissue plasminogen activators is used extensively in acute MI and, increasingly, in thrombotic stroke. Later we will discuss its (limited) place in VTE. Figure 1 illustrates the various interactions among the coagulation factors and naturally occurring anticoagulants. The left-hand box is often referred to as the coagulation cascade. It is better viewed as a mechanism of amplifying the initial stimulus for clotting, triggered by either: The extrinsic pathway (in which tissue factor directly activates factor VII, forming a complex, TF VIIa, in figure 1). The intrinsic pathway (in which initial contact with collage then ultimately activates factor XII). The common pathway for producing thrombin is the complex of activated factor X (Xa) and activated factor V (Va), which proceeds in the presence of Ca ++ and phospholipid (PL). Anti-thrombin III, not shown here, directly removes thrombin and many other activated clotting factors from the circulation. Its activity is markedly enhanced by heparin, either from intrinsic sources or administered therapeutically. Pathological clotting Venous thrombosis DVT (figure 2) occurs if a physiological clot formed within a deep vein propagates along the course of the vein beyond where it was generated. This happens when the factors promoting clotting overpower the factors limiting it. Its most important complication is embolism of friable clot along the venous system to the right ventricle and pulmonary arteries, which can cause sudden death. Table 1 lists its risk factors, as well as those for PE. The surgical or sick medical patient is in the classic high-risk situation for developing DVT. Patients undergoing lower limb joint replacement or hip fracture surgery are at the highest risk, with up to 60% incidence in unprotected patients. This obviously relates to the vessel injury part of Virchow s triad. Stasis is caused by slow re-mobilisation of surgical patients in all categories (particularly the elderly), and medical patients with stroke, cardiac failure, chronic obstructive pulmonary disease and similar conditions. Cigarette smoking and administration of excessive oestrogen (for contraception or poorly controlled HRT) increases the coagulability of plasma. The blood neoplasia polycythaemia vera and essential thrombocythaemia also increase blood coagulability, the former through hyperviscosity and the latter through increased numbers of platelets. The blood can be physically thickened by prolonged fasting with inadequate fluid replacement or the movement of intravascular fluid into the third space of transcellular fluid during wound repair and inflammation. Surgery or serious infection can also directly activate coagulation factors. Pregnancy activates coagulation factors and decreases thrombolysis. Factor Postoperative patient Cigarette smoking Oral contraceptive pill (OCP) Pregnancy Inflammatory bowel disease Cancer Long-distance air travel Figure 2: Deep venous thrombosis. Table 1: Risk factors for DVT and pulmonary embolism Basis Bed rest, vessel wall injury, inadequate rehydration Changes in the interaction between blood vessel wall and platelets Oestrogen-induced changes in both coagulation system and fibrinolysis As for OCP but compounded by anatomical factors. DVTs almost always in left lower limb Unknown Many cancers, particularly adenocarcinomas, have pro-coagulant material on their membranes, released at random into the circulation Cramped position for long periods Inactivity of lower limbs Fluid shifts associated with rapid changes in altitude Exacerbated by alcohol use The weight of the gravid uterus on the left iliac vein as it crosses below the external iliac artery produces the stasis that promotes DVT in pregnancy. Long-distance air travel also increases the risk of DVT. A longlegged person bent up like a paperclip in an economy-class seat has stasis in the lower limb veins. Travelling at an effective altitude of ,000m makes capillaries leak. Boggy ankles are a common complaint in air travellers and cabin staff; as the fluid that has seeped out of the capillaries is no longer in the veins, the blood in the veins is hyperviscous. Alcohol, so freely offered on international flights, further reduces spontaneous leg movement and increases dehydration. Inherited thrombophilia There are a variety of thrombophilic states, as shown in table 2 (page 36). As haemophilia produces excessive bleeding, so inherited thrombophilia is marked by excessive thrombosis. Currently we can find an explanation for recurrent or familial VTE in about 70% of cases. The obvious, though rarest, causes are inherited deficiency of anti-thrombin III, protein C or protein S. Much more common are polymorphisms in the factor V gene or the prothrombin gene, which render the proteins resistant to degradation. Persistence of thrombin or activated factor V allows propagation of the physiological clot up the lumen of the vein. The factor V Leiden polymorphism is the most common form of thrombophilia, affecting about 5% of Caucasian populations (increasing to 15% in some groups). A variation as common as this can hardly be called a mutation, although factor V Leiden often is. It is due to a single point nucleotide polymorphism (SNP) that results in the substitution of arginine by glutamine at a certain position on the factor V polypeptide chain. As this is the point where activated protein C (APC) cleaves activated factor V, the result is resistance to APC. John Griffin of the Scripps Clinic in California, who mapped the DNA sequences of the protein C and protein S genes, tells a gripping yarn about the investigation of APC resistance. Having demonstrated this SNP at an American conference, the Leiden group, headed by Pieter Rietsma, came forward from the audience and told him they had found the same thing in their lab. Some months later in 1994 both groups submitted their definitive papers to different journals in the same week. John Griffin s paper was held up in the peer review process, while the Leiden group s was passed and published promptly in Nature. John tells the story without rancour, but since then has always dealt with cont d page Australian Doctor 21 May

3 from page 34 peer review requests immediately, lest somebody else miss out on credit for hard work. Almost as common as factor V Leiden is the polymorphism in the prothrombin gene, commonly called the prothrombin gene G20210A mutation. This nomenclature signifies that the guanosine nucleotide at position has been substituted by adenosine, again producing a change in the polypeptide chain that renders the thrombin resistant to cleavage. This prothrombin gene polymorphism occurs in 2-4% of Caucasian populations. Both these resistance polymorphisms cause mild thrombophilia, compared with the rarer deficiency states. Anti-thrombin III deficiency is the most serious thrombophilic state yet described. All are inherited as autosomal dominant the individual only needs one resistant clotting factor gene for the clotting process to be prolonged. Similarly, a halving of the level of naturally occurring anticoagulants anti-thombin III, protein C or protein S will result in abnormal clot propagation. Obviously those who are homozygous or have two or more forms of thrombophilia are at higher risk of thrombosis. The thermolabile allele of methylene tetrahydrofolate reductase (MTHFR) is also associated with increased rates of venous and arterial thrombosis. Although this enzyme is obviously involved in folic acid metabolism, it also drives the conversion of homocysteine to methionine. Hyperhomocysteinaemia is associated with increased incidence of both arterial and venous thrombosis, but the mechanism of this is unknown. Because a slow MTHFR gene can be sped up by administration of folate (with or without B 6 and B 12 supplements), this diagnosis is worth making; it may be the only treatable form of inherited thrombophilia. An acquired, sometimes quite severe, thrombophilia arises in the phospholipid antibody syndrome. The antiphospholipid antibody interferes with the activated partial thromboplastin time (aptt) blood coagulation test, causing it to be prolonged (the lupus anticoagulant ). Yet at the vascular level this same antibody stimulates the formation of clots on the phospholipid membrane, a bit like how the auto-antibody in Grave s disease stimulates the thyroid gland. In practice phospholipid antibody syndrome is uncommon, most often seen in certain groups (young females, as with other autoimmune diseases) and is hard to confirm. A full-blown case will have both high-titre antiphospholipid antibodies and the lupus anticoagulant. In these cases there may even be a positive antinuclear antibody. Unfortunately, there is a lot of inter-laboratory variation in phospholipid (sometimes referred to as cardiolipin) antibody and lupus anticoagulant studies. So diagnosis is bedevilled by false-positive and false-negative laboratory tests. Table 2: Thrombophilic states Diagnosis Confirmatory test Comments Anti-thrombin III deficiency Protein C deficiency Protein S deficiency Myeloproliferative diseases Factor V Leiden Prothrombin gene mutation MTHFR** gene polymorphism Phospholipid antibody syndrome Anti-thrombin III level Protein C level Protein S level FBC Genetic studies Genetic studies Genetic studies Anti-phospholipid antibodies. Lupus anticoagulant Anti-thrombin-III levels drop in presence of active thrombosis: delay testing until treatment well underway As protein C is a vitamin K-dependent factor, do not test while patient is on warfarin As protein S is a vitamin K-dependent factor, do not test while patient is on warfarin Polycythaemia rubra vera controllable by venesection. Essential polycythaemia requires interferon or cytotoxics for control Obtain informed consent. # Can be done while patient on warfarin Obtain informed consent.* Can be done while the patient is on warfarin May or may not produce high homocysteine level. Treatable with folate supplements Diagnosis often subtle and hard to confirm *Genetic privacy is becoming a big issue. Some life insurance companies will refuse cover while others will load the premiums if the applicant answers yes to the question Have you ever had a genetic test? If they have and answer no, this may void the policy completely. **Thermolabile allele of methylene tetrahydrofolate reductase. Diagnosing venous thromboembolic disease THE first step in diagnosis is suspicion, that is, recognising the circumstances that can provoke DVT. These are outlined in table 1 in the previous section. However, many DVTs occur apparently spontaneously. Unprovoked DVT is more common in males, for some unknown reason. The typical DVT presents with pain and swelling in one calf. It is easy to pick these ones. More subtle presentations are more common, with painless swelling or unexplained pain. Physical findings in DVT are often subtle. The most important differential diagnosis is ruptured Baker s cyst. In PE you are more likely to find abnormalities in the heart (manifestations of right heart strain) than in the lungs. Chest X- ray is usually negative (figure 3). Similarly, PE presenting with pleuritic pain, tachycardia and hypoxaemia is straightforward a medical student diagnosis. More often only one of these is present in the history or needs to be teased out from other coexisting diseases. Several clinical scoring systems have been developed to help in diagnosing both DVT and pulmonary embolism. The most commonly used of these are the Wells score (tables 3 and 4). However, you should suspect DVT/PE in any at-risk patient and keep your eyes and mind open to the possibility in others. Investigations Figure 3: A: Pulmonary embolism (caudal view). B: Reconstruction (coronal plane). Philip Wells and colleagues published these rules for predicting DVT in A clinical scoring system for pulmonary embolism (table 4) was published by the same group in In 2003 these investigators showed that these clinical rules had 99.5% predictive value for excluding PE if the D-dimer test was negative. 4 Table 3: Wells score for clinical prediction of likelihood of DVT Variable Active cancer 1 Paralysis, paresis or plaster immobilisation of the lower extremities 1 Bedridden for three days or major surgery, within four weeks 1 Localised tenderness along the deep venous system 1 Entire leg swollen 1 Calf diameter more than 3cm larger on the symptomatic side 1 Pitting oedema greater on symptomatic side 1 Collateral non-varicose superficial veins 1 Alternative diagnosis more probable than DVT -2 Probability of DVT: low: 0 or less; intermediate: 1 or 2; high: 3 or more Table 4: Wells score for clinical prediction of likelihood of pulmonary embolism Clinical characteristic Score Previous pulmonary embolism (PE) or DVT +1.5 Heart rate >100 beats per minute +1.5 Recent surgery or immobilisation +1.5 Clinical signs of DVT +3 Alternative diagnosis less likely than PE +3 Haemoptysis +1 Cancer +1 Probability of PE: low: 0-1; intermediate: 2-6; high: 7 or more. Score INVESTIGATIONS are guided by your clinical assessment of the likelihood of DVT or PE is. A blood count is simple and will pick up occasional cases of myeloproliferative disease. A sensitive D- dimer test is also easy to do. An Australian-developed bedside D-dimer test (SimpliRED) is available in many hospitals and private labs. A negative D-dimer test tells you there is no active thrombosis/thrombolysis going on at the time and argues against a diagnosis of DVT or PE. A positive result is a little harder to interpret: thrombosis is part of the physiological inflammatory response, so postoperative patients will often have a positive D-dimer test. If there is a high clinical suspicion and a positive D-dimer test, further investigation is mandatory. DVT can be diagnosed in most cases by venous compression ultrasound with Doppler flow studies. Venography is rarely needed for confirmation. The standard for diagnosis of PE is now CT pulmonary angiography, using currentgeneration fast spiral CT scanners with a large bolus of IV contrast. This has virtually supplanted nuclear medicine for diagnosis of PE, except in patients who cannot have IV contrast because of allergy, renal impairment or coexisting treatment with metformin. 36 Australian Doctor 21 May

4 Management Initial treatment THE initial treatment of DVT and PE is heparin. Heparin works by pulling activated clotting factors out of the circulation, stopping clot propagation in its tracks. It should be started as soon as the diagnosis is suspected and need not be delayed while arranging confirmation with imaging studies. Patients in whom an iliofemoral DVT is compromising the circulation to the lower limbs (phlegmasia cerulae dolens or phlegmasia alba dolens) should be referred to hospital for consideration of thrombolytic therapy. Thrombolysis is also indicated in submassive PE (PE accompanied by arterial hypotension or acute right ventricular dysfunction). It is very important to use heparin first in the treatment of VTE. Warfarin is too slow to treat established thrombosis. In addition, warfarin reduces levels of protein C (a vitamin K-dependent factor) quite quickly, and so can initially promote clot propagation. Aspirin, for the reasons stated above, is almost useless in treating or preventing VTE. The form of heparin I recommend is enoxaparin (Clexane). All the low molecular weight heparins and the synthetic anticoagulant fondaparinux (Arixtra) share the advantages of subcutaneous administration, with no need for monitoring. Enoxaparin stands out as the most homogenous purified preparation. This has made it easy to prove that it is both safer and more effective than IV monitored heparin in numerous clinical trails. Paradoxically, heparin can sometimes cause thromboembolic events and thrombocytopenia (heparin-induced thrombosis with thrombocytopenia syndrome, HITTS). This syndrome results from the formation of antibodies to platelet factor 4, which is the heparin receptor. This antibody activates platelets to aggregate (often resulting in a thrombus) and in the process consumes platelets (resulting in thrombocytopenia). Fondaparinux is indicated in patients who have had proven HITTS. Fortunately this syndrome is becoming much less common now that low molecular weight heparins are routinely used, as they seldom provoke the antibodies that cause HITTS. This means, of course, that the patient with uncomplicated DVT does not need hospital admission. If the DVT is painful and the patient (eg, a young mother) cannot rest the affected limb, it is reasonable to admit them for bed rest until the pain has gone. Patients with PE should be admitted to hospital for the first three days of treatment, in case of repeat embolism. The usual dose of enoxaparin in patients with normal or near-normal renal function is 1mg/kg lean body mass SC bd. Several studies have shown that 1.5mg/kg once daily is equivalent to the bd dosing, but these involve relative small numbers of subjects. I recommend once-daily dosing if the patient cannot give themselves SC injections and needs home visits for the treatment. Secondary prevention with warfarin In virtually all cases of VTE, a course of warfarin should follow heparin for secondary prevention. I introduce warfarin at day 3 in shortsegment (below the knee) DVT, day 7 in full-length DVT and day 10 in DVT involving the internal iliac veins or in PE. Although the Therapeutic Guidelines approve earlier introduction of warfarin, it is better to use heparin alone for the first few days of treatment. Clinical studies based at McMaster University, Canada demonstrated the value of longer courses of heparin for more extensive thrombosis decades ago. Subcutaneous enoxaparin should be continued until the warfarin is at therapeutic levels, as demonstrated by an INR of >2.0. Most patients will have an INR of 1.0 at baseline. As the effect of warfarin on the INR takes seven days to fully show, I recommend twice-weekly INR testing until the warfarin is therapeutic, then weekly until the dose has been stabilised. Testing the INR too often is not only wasteful of resources, but also you will often end up chasing your tail with frequent dosage changes. Treatment with warfarin to maintain the INR in the range of is associated with a small risk of severe bleeding episodes: four per 100 patient-years in wellcontrolled clinical studies. The risk of bleeding complications increases dramatically if the INR is allowed to rise above 5.0. Home self-monitoring of INR is available, but not currently covered by Medicare. Duration of warfarin treatment This is a vexed question. Short-segment or postoperative DVTs have low recurrence rates after three months of warfarin, but we generally recommend at least six months of warfarin for long-segment DVTs and PE. The rate of recurrence of DVT is about 10-15% after cessation of warfarin. If the warfarin is continued for 12 months, this delays but does not eliminate recurrence. A promising approach was reported by Paraleti and colleagues in They measured D-dimer levels after completing a conventional course of warfarin. Subjects with a positive D- dimer test (presumably due to ongoing thrombotic or thrombolytic activity) had much higher rates of recurrent DVT than those with negative D-dimer tests. The D-dimer assay is not affected by warfarin. It seems reasonable to test D- dimer at the end of the conventional 3, 6 or 12 months of warfarin to guide the decision on whether to stop or to continue warfarin. There is some suggestion from recent literature that follow-up Doppler ultrasound studies of the lower limb can guide the decision to stop or continue warfarin in cases of DVT. This approach needs more investigation before it can be routinely recommended. It is not acceptable to continue warfarin indefinitely without a good reason, considering its significant risk of bleeding and the lifestyle restrictions it imposes on the patient. Alternatives to warfarin We are currently in the midst of a quiet revolution (to quote the current edition of Harrison s Principles of Internal Medicine) in management of VTE. At least three novel, orally active anticoagulants are in the active stages of development. They all share the advantages of fixed dosing and do not need to be monitored. Rivaroxaban (Xarelto) has been proven equivalent to Clexane for prevention of VTE after hip and knee replacement surgery, and is listed on the PBS for this indication. It is a direct inhibitor of the action of activated factor X (FXa). In addition to FXa inhibitors there are several orally active direct thrombin inhibitors. Of these, dabigatran (Pradaxa) is another alternative to Clexane for orthopaedic thrombo-prophylaxis, and is also PBS-listed. It is as safe and effective as warfarin for treating established VTE and probably equivalent to warfarin (perhaps better) in AF. The AF study, called the RE-LY study, has safety data going out to two years. It was published in September 2009, and discussion of its findings is still active. Hirudin is an injectable direct thrombin inhibitor, derived by DNA technology from the genes of the medicinal leech. Patients with active cancer have a significant rate of recurrent VTE on warfarin. For them, secondary prophylaxis with Clexane is recommended. Some may even need long-term Clexane at full therapeutic doses. Vena cava filters Patients with recurrent DVT who cannot be reliably maintained on warfarin or Clexane may be referred to a vascular surgeon for consideration of placement of a filter device in the inferior vena cava. Permanent filters protect against pulmonary embolism but are associated with high rates of postphlebitic syndrome. Temporary retrievable filters have a place to play in limited circumstances. Preventing post-phlebitic syndrome The post-phlebitic syndrome of pain, chronic venous insufficiency, skin thickening and staining is the complication of DVT that bothers patients the most. A properly fitted, fulllength graduated compression stocking (eg, TEDs) will halve the incidence of post-phlebitic syndrome. These should be used whenever the patient is ambulant for 12 months after the incident. It is of most benefit in patients with femoral or iliofemoral DVT. Recommending use of compression stockings for 12 months after the event is one of the best things you can do for the patient. Postphlebitic syndrome can be quite debilitating. Pregnancy and thrombophilia ANY of the thrombophilic states mentioned above can provoke VTE in pregnancy. However, some cases of VTE in pregnancy or the puerperium are not associated with any identifiable thrombophilic state. A much more important effect of thrombophilia is its association with infertility, recurrent mid-trimester abortion and intrauterine fetal growth retardation. All these may be due to thrombosis within the sinusoids of the placenta. All the thrombophilic states (and cigarette smoking) can cause placental insufficiency. The low-grade myeloproliferative disease essential thrombocythaemia (ET) can produce severe placental insufficiency. Be wary of this one: the platelet count tends to drop in the second trimester, so do not be misled by an apparent normalisation of the platelet count. If the first blood count in early pregnancy shows thrombocytosis (figure 4), the patient should be referred to a haematologist for assessment. Interferon is a safe and effective way of treating myeloproliferative disease such as ET in pregnancy. Infertility clinics routinely screen for maternal thrombophilia. Women Figure 4: Essential thrombocythaemia (ET). The blood film shows thrombocytosis, the platelets vary in size, and some of the red cells have abnormal shape, due to the underlying myeloproliferative process. The patient had symptoms of erythomelalgia (a hot, prickling sensation in the feet). This is unusual because we usually only see symptoms in patients with very high platelet counts (eg, > /L). The risk of thrombosis in ET rises dramatically when the platelet count is > /L. An important effect of thrombophilia is its association with infertility, recurrent mid-trimester abortion and intrauterine fetal growth retardation. with MTHFR gene polymorphisms are treated with folate, and vitamin B 12 and B 6 supplements regardless of their homocysteine levels, and I have seen one case in which this produced two successful pregnancies after three miscarriages. Women with a past history of thrombosis, recurrent miscarriage or stillbirth should receive prophylactic enoxaparin during pregnancy. In more severe forms of thrombophilia (eg, anti-thrombin III deficiency) this should start early and may even be increased to full therapeutic doses in the last trimester. Thromboprophylaxis should continue through delivery and into the puerperium in all cases. Current NSW Health policy for management of stillbirth includes the recommendation that the mother be offered thrombophilia screening. Despite all the above, we do not recommend routine thrombophilia screening of all pregnant women. It is simply not cost-effective unless there is a past history or family history of VTE or the woman has had previous pregnancy loss or recurrent pre-eclampsia. cont d next page 21 May 2010 Australian Doctor 37

5 Prevention of VTE Author s case studies Beware post-phlebitic syndrome MRS JM, 56, presented to the emergency department at her local hospital after two days of swelling of the left leg. She was an overweight nonsmoker with no past or family history of VTE. Doppler ultrasound studies confirmed a DVT extending the full length of the lower limb up to and including the external iliac vein. She was treated at home with seven days of enoxaparin 120mg daily, then warfarin was started, with enoxaparin continuing until her INR had reached 2.0. In view of the dusky discolouration of the limb, I considered thrombolysis but decided against it, as she did not have rest pain in the limb. I wish I had, because despite 12 months of warfarin and conscientious use of full-length compression stockings, she now has a bad case of post-phlebitic syndrome. Acute dyspnoea and chest pain after depression Mr JH, 72, had developed depression 12 months before hospital presentation and had gained 12kg during antidepressant therapy. His wife commented that, despite an improvement in his mood, he didn t move around much anymore. He presented with a one-day history of dyspnoea and mild pleuritic chest pain. Physical examination, chest X- ray and ECG were normal. D-dimer test was positive, so he was referred for CT pulmonary angiogram. This demonstrated multiple filling defects in the pulmonary arteries, as indicated in the image. He was treated with enoxaparin 1mg/kg bd for three days in hospital, then discharged to continue it at 1.5mg/kg once daily at home for a further seven days before warfarin was introduced. He made an uneventful recovery and echocardiogram at six months showed normal right heart pressures. As far as I can tell, the only background risk factors in this case were overweight and inactivity. Thrombophilia testing was not performed. Exercise caution if thrombocythaemia normalises in pregnancy Mrs GH, 26, was found to have a high platelet count on routine testing. Bone marrow examination confirmed essential thrombocythaemia but, as the platelet count was /L, no treatment was prescribed. GH attended her haematologist for regular follow-up and 18 months after diagnosis informed him that she was pregnant. Her platelet count fell to /L at week 22 of pregnancy and her GP and obstetrician told her that the ET was in remission and she need not continue to make the long journeys to see the haematologist. The baby was born small for dates, with low APGAR scores and extensive thrombus formation on the placenta. He progressed slowly in infancy and four years later it became apparent that he had severe learning difficulties. In retrospect, the drop in platelet count during the second and third trimester was obviously due to platelet pooling in the placental circulation (similar to what happens in the spleen of patients with portal hypertension). GH should have been advised to continue seeing her haematologist during pregnancy, and he would probably have prescribed enoxaparin from 28 weeks on. The safety of alpha-interferon in pregnancy had not been proven at that time, but has subsequently and so is now a reasonable treatment for myeloproliferative disease in pregnancy. Cytotoxics are not used in pregnancy because of their mutagenic and teratogenic effects. ANYBODY who has had a previous episode of VTE is vulnerable to another in the circumstances listed in table 1 (page 34). However, not everybody with an inherited thrombophilia develops VTE. This varies from about 50% of cases of the most severe thrombophilia (antithrombin III deficiency) down to quite low percentages of the common, less severe types, such as factor V Leiden and the prothrombin gene polymorphism. In hospitalised patients the risk of VTE is highest in hip fracture, lower limb joint replacement surgery and immobile stroke patients. Almost any surgery even putting a plaster cast on the lower leg is associated with an increased risk of VTE, but risk stratification according to type of surgery and patient factors is recommended. For lower-risk patients, a smaller dose of enoxaparin (20mg daily) is recommended, starting the evening after surgery. For hip fracture or replacement patients, enoxaparin 40mg, fondaparinux 2.5mg or oral rivaroxaban 10mg/day should be continued daily for a total of days after surgery. In the case of enoxaparin, the evidence favours giving the first dose hours before surgery. Practice points Graduated compression stockings, early remobilisation and intermittent calf compression or foot impulse during surgery are additional routinely used precautions in hospitalised patients. In the general community, people with a past history of recurrent VTE or proven thrombophilia should be advised to maintain ideal weight and exercise regularly. If confined to bed by intercurrent illness for more than two days they should have chemical thromboprophylaxis and maintain a high fluid throughput. All overseas travellers should perform the in-seat exercises recommended by the airlines and take plenty of (non-alcoholic) fluids during the flight. Some authorities recommend walking around the cabin during level flight but Australian guidelines do not. The potential harm that can be done by clear-air turbulence makes the in-seat exercises a better option. Patients with a past history of VTE or confirmed thrombophilia should be given a letter of explanation so that they can be seated with plenty of leg room, and should be advised to have a 40mg dose of enoxaparin just before each flight lasting four hours or longer. Those who cannot self-inject could be prescribed rivaroxaban or dabigatran at their own cost. Aspirin is of no benefit in preventing VTE in air passengers and increases the risk of gastrointestinal haemorrhage. Doctors at the Charles de Gaulle Airport Medical Centre in Paris reported a direct correlation between the distance travelled by air and the incidence of post-flight VTE. Several years later they wrote to the same journal urging readers not to use aspirin for thromboprophylaxis, as they were now seeing an epidemic of upper GI haemorrhage induced by aspirin in airline passengers. Venous thrombosis arises in the setting of Virchow s triad: stasis; blood vessel injury; and blood that is either physically hyperviscous or has a constitutional tendency to increased coagulation. Arterial thrombosis results from platelet activation in high-shear turbulence beyond an arterial occlusion. Treatment of each differs fundamentally therefore: VTE is treated by anticoagulation; arterial pathology is treated with platelet-function antagonists such as aspirin. Normal haemostasis is triggered by either external material (tissue factors) or intravascular activity of activated enzymes. The initial trigger to form a clot is amplified by activation of other coagulation factor precursors. The same enzyme activity that activates pro-coagulant activity where the clot is needed also activates enzymes that limit the size of the resulting clot. A physiological clot can propagate to become a pathological thrombosis if the balance between clot formation and breakdown is disturbed. Single nucleotide polymorphisms conferring resistance by a clotting factor to normal degradation are common causes of thrombophilia. Rarer causes of this imbalance are simple deficiency states. The Wells score guides clinical judgement in possible VTE. D-dimer assays are useful if negative. Doppler ultrasound is the best way to confirm DVT. Fast CT scanning is supplanting nuclear medicine for diagnosis of PE. Heparin works immediately whereas warfarin takes several days to work. Subcutaneous low molecular weight heparins are at least as safe and effective as intravenous monitored unfractionated heparin. For DVT, the heparin phase of treatment can be done at home. The duration of secondary prophylaxis with warfarin is ill-defined. Superior anticoagulants are in rapid development at present. Constitutional thrombophilia is an important cause of recurrent loss of conceptus. LMWH is safe and effective treatment of thrombosis in pregnancy. Placental function in late pregnancy should be actively monitored in women with constitutional thrombophilia. Patients with previous VTE, whether due to identified thrombophilia or not, are at high risk of further VTE during pregnancy, severe medical illness, elective surgery or overseas air travel. Effective prevention addresses all parts of Virchow s triad. People with a history VTE should be given written instructions if travelling long distances. References 1. Decousus H, et al. Superficial venous thrombosis and venous thromboembolism: a large, prospective epidemiologic study. Annals of Internal Medicine : Wells PS, et al. Value of assessment of pretest probability of deep-vein thrombosis in clinical management. Lancet 1997; 350: Wells PS, et al. Use of a clinical model for safe management of patients with suspected pulmonary embolism. Annals of Internal Medicine 1998; 129: Wells PS, et al. Evaluation of D-dimer in the diagnosis of suspected deep-vein thrombosis. New England Journal of Medicine 2003; 349: Palareti G, et al. D-dimer testing to determine the duration of anticoagulation therapy. New England Journal of Medicine 2006; 355: Further reading Dahlbäck B. Advances in understanding pathogenic mechanisms of thrombophilic disorders. Blood 2008; 112: The Australia and New Zealand Working Party on the Management and Prevention of Venous Thromboembolism. Prevention of Venous Thromboembolism: Best Practice Guidelines for Australia & New Zealand. 4th edn. Health Education and Management Innovations, NHMRC. NHMRC Clinical Practice Guideline for the Prevention of Venous Thromboembolism in Patients Admitted to Australian Hospitals. NHMRC, Canberra, Online resources Resources produced by the Australasian Society of Thrombosis & Haemostasis: The Australian Government s Health Insite program: ics/deep_vein_thrombosis The US National Heart, Lung & Blood Institute has very accessible material for the general public: dci/diseases/dvt/dvt_ WhatIs.html cont d page Australian Doctor 21 May

6 GP s contribution DR HANI BITTAR Glendenning, NSW Case study LS, 19, presented for advice on contraception, as she and her boyfriend have decided to be a couple. She has never used any contraceptive before this consultation. After a lengthy discussion she decided to try the oral contraceptive pill. She was given a script for a triphasic pill and counselled on how to use it and the possible side effects. Later that week she called the after-hours service complaining of low back ache radiating to her left leg, she was diagnosed with left sciatica and given paracetamol with codeine. She rang her GP the following day to inform him of her pain and what she was told by the after-hours doctor and was advised to go to the radiologist and have a lumbar spine CT. This was reported as normal. By day 3 she was complaining of a painful swollen left thigh, and a Doppler U/S revealed extensive DVT reaching up to the common iliac vein. She was referred to accident and emergency to start anticoagulation therapy and was advised not to use oestrogen-containing pills in the future. Questions for the author LS had no past or family history of extensive thrombosis. Are there any measures to predict such an event in an otherwise healthy young woman? Unfortunately not. Cigarette smoking is an important contributor. What is the place of thrombophilia screening in pregnancy, especially with habitual miscarriage, and what tests should a GP order? Thrombophilia testing, using the tests listed in table 2, is an essential part of investigating recurrent pregnancy loss. Routine testing of all pregnant women is not recommended. In elderly patients treated for DVT with warfarin, what is the best test you could order to stop warfarin treatment safely? I usually perform a D- dimer test at the end of six months, discontinue the warfarin if the test result is negative, then repeat the D- dimer test one month later to be sure. If the test is positive, continue warfarin and repeat the procedure another six months later. How to Treat Quiz 21 May 2010 INSTRUCTIONS Complete this quiz online and fill in the GP evaluation form to earn 2 CPD or PDP points. We no longer accept quizzes by post or fax. The mark required to obtain points is 80%. Please note that some questions have more than one correct answer. ONLINE ONLY for immediate feedback 1. Which THREE statements are correct? a) Arterial thromboembolism, from left atrial thrombus secondary to chronic or intermittent atrial fibrillation, should be managed using the principles for arterial thrombosis b) Superficial thrombophlebitis may be associated with DVT or pulmonary embolism (PE) at presentation or later c) Blood vessel injury exposes platelets to collagen and other substances in the vessel wall, resulting in rapid platelet activation and aggregation, plugging the hole in the vessel wall d) Platelet activation and exposure of the plasma to tissue factors activate the plasma clotting factors, which in turn leads to production of thrombin from prothrombin 2. Which THREE statements are correct? a) Thrombin is pro-coagulant; it cleaves soluble fibrinogen into fibrin which, with platelets and red cells, forms the basis of a soft clot b) Thrombin limits coagulation; it activates such enzymes as protein C, protein S and plasminogen, which in turn inactivate clotting factors and limit the extent of the thrombus c) D-dimer is produced from fibrin degradation only in the clinical setting of DVT d) Synthetic tissue plasminogen activators generate plasmin, which limits or dissolves a clot 3. Which THREE statements are correct? a) Heparin enhances the activity of antithrombin III b) Patients undergoing lower limb jointreplacement or hip fracture surgery are at the highest risk of DVT or PE, with up to 60% incidence in unprotected patients c) Clinical situations in which stasis is an important cause of thrombosis include slow remobilisation of surgical patients and medical patients with stroke, cardiac failure, chronic obstructive pulmonary disease, and compression of the left iliac vein by the gravid uterus d) The coagulability of blood can be increased by polycythaemia rubra vera, prolonged fasting with inadequate fluid replacement, or the movement of intravascular fluid into the third space of transcellular fluid as a result of wound repair and inflammation 4. Which THREE statements are correct? a) Factors that predispose to DVT in longdistance air travel include stasis (immobility of lower limbs) and increased blood viscosity (due to dehydration and altitude-related fluid shifts) b) The most common inherited causes of thrombophilia are deficiency of anti-thrombin III, protein C or protein S c) Polymorphisms in the factor V gene or the prothrombin gene render these two procoagulant proteins resistant to degradation, pre-disposing to thrombus propagation d) Causes of inherited thrombophilia due to deficiency of factors tend to be more clinically severe than causes due to polymorphisms 5. Which THREE statements are correct? a) An abnormal methylene tetrahydrofolate reductase (MTHFR) gene, which is associated with venous and arterial thrombosis, can be treated with folate supplements b) In the phospolipid antibody syndrome, the antibody interferes with the aptt blood coagulation test, causing it to be prolonged (the lupus anticoagulant ) and causes abnormal bleeding c) In the phospholipid antibody syndrome, the antibody stimulates the formation of clots on the phospholipid membrane and causes increased thrombosis d) In PE, abnormalities are more evident in the heart (such as manifestations of right heart strain) than in the lungs 6. Which THREE statements are correct? a) The Wells score for clinical prediction of DVT risk includes only lower-limb signs related to DVT b) When a D-dimer test is negative, the Wells score for clinical prediction of PE risk can accurately exclude PE c) The Wells scoring systems for DVT and for PE can accurately guide the need for further investigations d) Blood tests for DVT or PE include FBC and D-dimer 7. Which THREE statements are correct? a) A negative D-dimer test argues against a diagnosis of DVT or PE b) A positive D-dimer test indicates there is a DVT or PE c) The standard investigation for the diagnosis of PE is CT pulmonary angiography using current-generation fast spiral CT scanners with a large bolus of IV contrast d) V/Q nuclear medicine scanning for the diagnosis of PE is appropriate in patients who cannot have IV contrast because of allergy, renal impairment or coexisting treatment with metformin 8. Which TWO statements are correct? a) Diagnosis of DVT or PE should be confirmed with imaging studies before starting treatment with heparin b) Thrombolytic therapy is indicated in submassive PE and should be considered in patients in whom an iliofemoral DVT is compromising the circulation to the lower limbs c) Warfarin quickly reduces levels of protein C (a vitamin K-dependent factor) and thus can initially promote clot propagation d) Aspirin is an alternative to warfarin in the treatment or prevention of DVT or PE 9. Which THREE statements are correct? a) Enoxaparin has the advantages of subcutaneous administration, no need for monitoring, and increased safety and efficacy compared with intravenous heparin b) Heparin can sometimes cause thromboembolic events and thrombocytopenia c) Warfarin should be started for secondary prevention of DVT or PE after stopping heparin d) A positive D-dimer test towards the end of a course of warfarin may indicate ongoing thrombotic/thrombolytic activity and that the patient is at greater risk of recurrent DVT than a patient with a negative D-dimer test 10. Which TWO statements are correct? a) There are no effective treatments for the prevention of post-phlebitic syndrome b) In a pregnant woman with elevated platelet counts in early pregnancy, the platelet count may appear to normalise in the second trimester, obscuring the important diagnosis of essential thrombocythaemia c) Women with a past history of recurrent miscarriage or stillbirth should be screened for thrombophilia d) Aspirin prevents VTE in air passengers CPD QUIZ UPDATE The RACGP requires that a brief GP evaluation form be completed with every quiz to obtain category 2 CPD or PDP points for the triennium. You can complete this online along with the quiz at Because this is a requirement, we are no longer able to accept the quiz by post or fax. However, we have included the quiz questions here for those who like to prepare the answers before completing the quiz online. HOW TO TREAT Editor: Dr Giovanna Zingarelli Co-ordinator: Julian McAllan Quiz: Dr Giovanna Zingarelli NEXT WEEK Pacing devices are increasingly common and important life-saving devices, especially as the population ages. In Australia, the number of patients with pacemakers continues to increase exponentially, and as pacemakers become more sophisticated, understanding their role in management is an increasing challenge. Keep pace with the latest developments in next week s How to Treat on this fascinating topic. The author is Dr Edward Barin, senior consultant cardiologist, department of medicine, and director of the pacemaker and implanted devices clinic, Royal North Shore Hospital, St Leonards; and adjunct professor, University of Technology, Sydney, NSW. 40 Australian Doctor 21 May