Drugs affecting blood coagulation and hemostasis

M. Verstraete and J. Vermylen

37

Drugs affecting blood coagulation and hemostasis

HEPARIN (SED-IO, 665; SEDA-8, 328;

SEDA-9,304; SEDA-10,313; SEDA-11,317) (SED-10,666; SEDA-10,314; SEDA-11,317) There is Heparin-induced thrombocytopenia

considerable confusion around the heparinplatelet interactions often lumped together as 'heparin-induced thrombocytopenia'. A nonidiosyncratic interaction, usually immediate in onset, should be distinguished from a delayed idiosyncratic heparin-platelet interaction resuiting in thrombocytopenia alone or in combination with acute arterial thrombosis (1R). The acute, non-idiosyncratic heparin-platelet interaction is a heparin-induced platelet aggregation which may result in a transient drop in platelet count and prolongation of bleeding time. This reaction depends on the characteristics of the heparin preparation (particularly on the presence of high-molecular-weight heparin fractions) and varies considerably among individuals. The idiosyncratic heparin-induced thrombocytopenia, complicated or not by arterial thrombosis, occurs between day 7 and 11 of treatment and is more frequent with bovine heparin and after previous exposure to heparin; in the latter case thrombocytopenia also develops sooner, suggesting an amnestic response. Heparin may act as a hapten and induce an immune response against the platelet-heparin complex. This would explain why delayed idiosyncratic heparin-induced thrombocytopenia is not dosedependent and can also occur after subcutaneous injections and even from heparin flushes (2c). An analog of heparin, pentosan polysulfate, is a low-molecular-weight sulfated polysaccharide which may also induce thrombocytopenia and arterial thrombosis (3c; see also SEDA-11,317). If heparin can injure the platelets, it is surprising that spontaneous bleeding develops so rarely despite the presence of heparin and Side Effects of Drugs Annual 12

M.N.G. Dukes and L. Beeley, editors 9 Elsevier Science Publishers B.V., 1988

occasional very low platelet counts. An attractive hypothesis is that heparin-dependent antibodies bind to platelets as well as to endothelial cells; the platelet-endothelial cell interaction may trigger the release of procoagulants from the vessel wall, predisposing to thrombosis (4R). Antibody-induced platelet aggregation is not a passive agglutination but an active process requiring metabolic energy which is prostaglandin- and ADP-dependent. This explains why aspirin combined with dipyridamole can in most cases suppress the in vitro aggregation induced by the serum of affected patients (5c). Management of idiosyncratic thrombocytopenia demands immediate discontinuation of heparin; aspirin combined with dipyridamole may be helpful. Fibrinolytic treatment has been instituted successfully in cases of occlusive thrombosis (6c, 7c). When urgent surgery is required in patients with idiosyncratic thrombocytopenia, use of plasmapheresis and high-dose gammaglobulin can be considered (8c).

(SED-I0,667; SEDA-8, 329; SEDA-11,317) HypersensitiviHeparin-induced skin necrosis

ty reactions to unfractionated or low-molecularweight heparin continue to be reported; they may induce a global cardiovascular collapse (SEDA-11,317; 9 c) or be limited to necrosis of the skin overlying the injection sites or cause distant cutaneous necrosis, without any site of predelection. Histological examination suggests an Arthus-type reaction with the formation of antigen-antibody complexes, with or without deposition of aggregated platelets. It is interesting to note that intradermal tests with different brands ofheparin give positive delayed reaction responses; however, patch tests using only the antimicrobial preservative chlorbutal, as used in commercial heparin preparations, produce no response (10R), apparently disproving an earlier hypothesis that this preservative was responsible for skin lesions (SED-10,665; SEDA-I 1,317), Large hematomas of the abdominal wall can even occur after lowRare bleeding complications

310 dose calcium heparin and become a lifethreatening complication (1 lC). Above the umbilicus, they present as unilateral masses confined by the rectus sheath. Below the linea semicircularis, the rectus sheath lacks a posterior wall and hemorrhage can dissect extensively and resemble a pelvic mass.

Effect of heparin on lipoprotein lipase In addition to its anticoagulant effect, heparin releases lipoprotein lipase from adipose tissue and skeletal muscle. The resultant lipoprotein lipase catabolism of serum lipoproteins yields lipid remnants that are processed rapidly by the liver and at extrahepatic sites. Patients with dysbetalipoproteinemia (Type III hyperlipidemia) are unable to catabolize these lipid remnants, and their accumulation can cause serious hyperlipidemia (12c), i.e. such patients comprise a special risk group.

Suppressive effect of heparin on aldosterone production (SED-IO, 666; SEDA-11, 317) The suppressive effect of full-dose heparin (20,000 IU/d or more) on adrenal aldosterone production, with resultant hyperkalemia, is well known; a similar inhibitory effect is also obtained with low-dose heparin (SEDA-11,317). Five healthy male volunteers were given 5000 IU heparin subcutaneously every 12 hours for 10 days. Plasma aldosterone fell from 11.5 #g/100 ml at baseline to 6.6 #g/100 ml on day 5 and to 4.3 #g/100 ml on day 10. The 24-hour urinary aldosterone fell from 11.5 #g/d at baseline to 5.3 and 6.8 #g/d on days 5 and 10 respectively. After stimulation with furosemide and ambulation, plasma aldosterone remained suppressed on heparin (13c). Hospitalized patients with congestive heart failure or acute myocardial infarction commonly receive digitalis, diuretics, and low-dose heparin. The likelihood of heparin-induced hyperkalemia may be particularly increased when potassium-sparing diuretics are used. After heparin is discontinued, these patients may be at risk for hypokalemia and cardiac arrhythmia from enhanced kaliuresis; in addition, sodium retention and worsening congestive heart failure may result from diminished natriuresis.

Depression of anticoagulant effect of heparin by propyleneglycol Propylene-glycol-induced heparin resistance during nitroglycerine infusion has been reported at doses used in coronary care units (14c). The prolongation of coagulation tests is decreased by approximately 50 %.

Chapter 37 M. Verstraeteand J. Vermylen It is important to note that most commercial nitroglycerine preparations are diluted in alcohol and propylene glycol, and under intensive care conditions this interaction could be clinically significant.

Interference with diagnostic tests Heparin preparations of bovine or porcine origin can, independent of the route of administration, induce a reversible increase in serum aminotransferases (SEDA-10, 314; SEDA-11,318). A two-fold increase in ~-glutamyl transpeptidase with maximal values after 7 days treatment has also been observed without an increase in serum levels of alkaline phosphatase or thrombocytopenia (15c). A progressive return to normal enzyme concentrations follows in 3 days after maximal values have been reached; they may normalize after drug withdrawal and even despite its continuation. The cause of transiently increased transaminases associated with heparin therapy is probably subcellular damage in the liver. Synergistic effect of unfractionated or fractionated heparin and dihydroergotamine (SEDA8,329; SEDA-IO, 314; SEDA-11,317) There is strong evidence that the combination of lowdose heparin and dihydroergotamine prevents postoperative deep vein thrombosis more effectively than either drug alone. It has also been shown that this combination equals dextran in prophylaxis of fatal pulmonary embolism even in orthopedic patients and after hip fracture as well as in other high-risk postoperative conditions (for a recent review, see 16R). AS reported earlier, however (SEDA-10, 314; SEDA-11,317), there is the risk of severe vasospasm and skin necrosis following administration of even small doses of dihydroergotamine (3 x 0.5 mg/d). The incidence of vasospasm is stated to be between 0.02 and 0.2%. There is no doubt that certain categories of patients are more prone to this complication as discussed in detail (SEDA-10, 314); particularly in traumatic disorders, during pregnancy and oral contraception, the risk of vasospastic reactions appears to be increased (17c). More recently, much interest has been focused on the prophylactic effect of low-molecularweight heparin fragments combined with dihydroergotamine (18c). One daily dose of the latter preparation was equally effective and as safe as the twice-daily regimen using a combination of unfractionated heparin and dihydroergotamine in patients undergoing elective major abdominal surgery.

Drugs affecting blood coagulation and hemostasis Chapter 37

Low-molecular-weight heparin fractions and fragments (SEDA-9, 305) Unfractionated heparin represents a heterogeneous mixture of highly sulfated acid polysaccharide chains of varying length and chemical composition, with a molecular weight range of 1500-30,000 daltons (mean 15,000 daltons). Unfractionated heparin is also highly heterogenic as regards antithrombin III binding capacity; only 30 % is bound to antithrombin III with high affinity. Using high-affinity heparin, fractions have been produced by various physicochemical techniques; their molecular weight ranges from 1500 to 8000 daltons. Fractions with a molecular weight over 5000 daltons exert an inhibitory effect against Factor Xa and thrombin ; those of lower molecular weight have predominantly an anti-Factor Xa effect. Since Factor Xa in circulation is generated at lower concentrations than thrombin, its inhibition is more readily obtained. Moreover, the generation of Factor Xa occurs earlier in the coagulation cascade than thrombin formation; inhibition of the activation of 1 molecule of Factor X will ultimately prevent the generation of considerably more molecules of thrombin. An increasing number of low-molecular-weight heparin fractions and fragments are becoming available for clinical studies. These molecules all have a molecular weight around 5000 daltons ; they are obtained by a variety of physicochemical methods and vary in their bioavailability, antithrombotic potential and bleeding-inducing characteristics. In the absence of an agreed international standard, the manufacturers use house units or define their products using different assays (19R). To rely on dry weight as a measure of dosage wouM not solve this critical problem. More experience is required to establish with certainty that lowmolecular-weight heparin at effective prophylactic doses is associated with a lower bleeding incidence and induces less thrombocytopenia than regular beparin. A definite advantage is that a single daily subcutaneous injection seems to provide adequate antithrombotic prevention.

COUMARIN CONGENERS (SED-IO, 668; SEDA-8, 329; SEDA-9, 305; SEDA-IO, 315; SEDA-I l, 318)

Skin necrosis induced by coumarin drugs Skin necrosis is a rare but well-documented complication of anticoagulant therapy, particularly with oral anticoagulants and most often during

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the first 5 days of anticoagulation but also at times of excessive hypocoagulability during long-term coumarin treatment (20c). Among several predisposing factors, a pre-treatment low level of protein C or S seems to be the most important. Protein C is a vitamin-K-dependent glycoprotein that functions as an anticoagulant; protein S is a cofactor for the action of protein C and is also vitamin-K-dependent. Individuals with a deficient or functionally defective protein C or S thus comprise a risk group: they have a precarious balance between normal levels of the vitamin-K-dependent procoagulant Factors II, VII, IX and X and reduced levels of protein C or S. This imbalance is exaggerated during initial administration of warfarin; when synthesis is inhibited, blood levels of proteins fall in proportion to their biological half-lives, and proteins C and S have a shorter half-life than Factors II, IX and X. It has been shown that despite protein C deficiency and previous warfarin necrosis, oral anticoagulation can safely be reinstituted using progressive doses of a long-acting oral anticoagulant (phenprocoumon) while maintaining a safe level of protein C with fresh frozen plasma infusions until the desired inhibition of all functional vitamin-K-dependent factors has been achieved (21c).

Life-threatening bleeding complications The most dangerous complication during anticoagulant treatment is intracranial bleeding (SED-10,312; SED-I1,317); the risk of an intracerebral or subdural hematoma is multiplied by 10 in patients over 50 years of age on long-term treatment with oral anticoagulants when compared with untreated individuals in the general population. Eleven percent of all intracranial bleedings and 12-38~ of all subdural hematomas occur during anticoagulant treatment (22c). At least 50 % of all intracranial hemorrhages are fatal.

Rare but possibly underdiagnosedbleeding complications Spontaneous mediastinal bleeding with no underlying pathological condition is a rarelyreported complication of anticoagulantor thrombolytic treatment (SED-10,311). The true incidence is probably many times greater due to the difficulty in diagnosing mild bleeding in the mediastinum, as changes in mediastinal width may remain unrecognized because of lack of previous X-ray films. Spontaneous tamponade usually intervenes before major cardiac problems arise and the prognosis is good (23c). Mediastinal hemorrhage should be included in

312 the differential diagnosis of chest pain in anticoagulated patients, particularly if the diagnosis of myocardial infarction is considered, because of the growing use ofthrombolytic agents to treat the latter condition. Intestinal hemorrhage within the bowel wall is so far not a frequently reported complication during anticoagulant treatment. Newer diagnostic approaches such as endoscopy, ultrasonography and computed tomographic scanning of the abdomen help to establish the correct diagnosis more readily in patients with ileus or subileus. Proper recognition will usually render abdominal surgery unnecessary in these very compromised patients (24c-26c). Hemorrhagic compression of thefemoral nerve is a well-known complication in hemophilic patients, but is also very occasionally seen as a complication of anticoagulant treatment. The femoral neuropathy is attributable to progressive subfascial bleeding leading to a compartmental syndrome (27c). The earliest symptoms are burning pain in the inguinal region, radiating to the thigh and flank, followed by increasing loss of tactile sensation on the anteromedial surface of the lower limbs. A quadriceps muscle paralysis with absence of the patellar reflex is the ultimate stage. This bleeding is now easily recognized by computed tomographic scanning. Conservative treatment is generally recommended, but surgical decompression can be considered (28c). A sublingual hematoma or parapharyngeal hemorrhage are indeed rare complications of oral anticoagulation. All cases so far reported have required intubation, tracheostomy or cricothyroidotomy because of airway obstruction (29 c, 30c). Prompt diagnosis is essential to prevent the development of acute airway obstruction. Although cases of salpingitic and labyrinthine bleeding have been associated with oral anticoagulant treatment, hemorrhage into the tympanic membrane without preceding trauma causing a sudden but temporary hearing loss has now been reported (31c). Hematuria associated with oral anticoagulant therapy is accompanied by an obvious causal lesion in only half the cases; the rest are assumed to be due to excessive anticoagulation. The recent identification of a vitamin-K-dependent inhibitor of calcium oxalate nephrolithiasis (32 r) may explain the propensity to form microscopic calcium oxalate stones inducing

Chapter 37 M. Verstraeteand J. Vermylen microscopic bleeding during warfarin treatment (33r).

Idiosynchratic cholestatic hepatic injury related to warfarin (SED-IO, 669) In the past there have only been some 6 reported cases of cholestatic hepatic injury due to warfarin sodium and 10 due to phenprocoumon. A new and extremely well-documented case with inadvertent rechallenge has been described (34c). The criteria for idiosyncratic drug injury such as temporal compatibility, the response to rechallenge and absence of other forms of drug exposure or pathological causes were all fulfilled. THROMBOLYTIC DRUGS (SED.IO, 670; SEDA-8, 330; SEDA-9, 306; SEDA- 1O, 316)

Streptokinase The rapid infusion of a high dose of streptokinase, but also of urokinase and of tissue-type plasminogen activator, may induce a transient hypotensive effect. In a prospective study of 101 consecutive patients with acute myocardial infarction 750,000 IU of streptokinase were administered over 30-60 minutes. The blood pressure values fell from 132/80 to 97/61 mmHg at 15 minutes after the commencement of streptokinase infusion, but hypotension lasted for only about 10 minutes (35c). In hemodynamically compromised patients and in those with a baseline systolic pressure of less than 100 mmHg, it is advisable to commence the infusion at a slow rate of 200-250 IU/kg/min or less and to have an infusion of noradrenaline available 'on standby'. The hypotension may be due to plasmin activation of kallikrein or of the complement pathway, production of bradykinin, or endothelial stimulation of prostacyclin. Streptokinase may induce allergic reactions with a frequency of 1.7-18~. Generalized immediate-type hypersensitivity reactions, formation of toxic immune complexes, and delayed cutaneous lymphocytic reactions have all been described (SED-10, 316). Anaphylaxis may be modified by antihistamines or considerably reduced by corticosteroids given several hours before streptokinase treatment. An intradermal test with 100 IU ofstreptokinase allows identification of patients at risk for anaphylaxis to this agent (36c).

Drugs affecting blood coagulation and hemostasis Chapter 37

Anisoylated plasminogen streptokinase-activatorcomplex (APSAC) p-Anisoylated human plasminogen streptokinase-activator complex (APSA C) is an acylated complex of streptokinase with human lysine-plasminogen. Acylation of the catalytic site of plasminogen delays the formation of the fibrinolytic enzyme plasmin, but has no influence on the lysine-binding sites involved in binding the complex to fibrin. Deacylation commences immediately after intravenous injection. The main advantage of APSA C is that this agent is suitablefor intravenous administration over 5 minutes, in contrast with the prolonged infusion required with intravenous streptokinase. In addition, its fibrinolytic action is theoretically selective for fibrin associated with thrombi ; however, in practice, systemic fibrinolysis does occur in patients to almost the same extent as with streptokinase. A well-documented recent review on APSAC is worth reading (37R). In comparative trials evaluating APSAC (30 U injected as an i.e. bolus) and streptokinase, in most cases intravenously administered in high dose (1,500,000 IU over 30 rain), the repeo~ion rate, as assessed using repeated coronary angiograms, was 67% (155/232 patients) with APSAC compared with 65% (92/141 patients) with streptokinase. Among patients who were reperfused with APSAC and in whom coronary angiography was performed 24-72 hours after treatment, there was reocclusion in only 2 of 58 patients (3.4 %); the corresponding reocclusion rate after intracoronary or intravenous streptokinase was 5 of 66patients (7.6%). Hemorrhagic events were reported in 9% of the patients receiving APSAC and 10.7% of the patients receiving streptokinase in comparative studies (38a). In trials comparing APSAC with intracoronary streptokinase (1.6 x I05 U over 60 rain), the mean fibrinogen concentration (as a percentage of pre-treatment values) at 90 minutes after treatment was 38.7 % in patients treated with APSAC and 63.9% in patients treated with streptokinase (39s). The greater fibrinogen reduction after APSA C may be accountedfor by the different routes of administration as well as the

313

dosages used. Similar results were obtained in another multicenter trial comparing APSA C (30 U) with a higher dose of intracoronary streptokinase (2.5 x I0 J U over 60 rain). In comparative trials of APSA C (30 U) versus intravenously infused streptokinase (1.5 x 10~ 1U over 60 rain) the same reduction in ftbrinogen concentrations and the same incidence of adverse events were noted in the two treatment groups (40R-42a). Recombinant human tissue-type plasminogen activator (rt-PA)

This novel and more fibrin-specific thrombolyric agent, given in doses ranging from 80 to 100 mg is effective in producing higher coronary patency rates than placebo or intravenous streptokinase in a dose of 1,500,000 U (43 s, 44R). Large-scale studies on leR ventricular function or mortality have not yet been published. Hemodynamic upsets or allergic reactions have not been encountered. Most patients treated with doses of 0.75 mg/kg show some degree of systemic fibrinogen depletion, but this is seldom severe. With this dose, the rate of bleeding complications is higher than in patients receiving heparin alone but lower than in those given streptokinase (45R). With 50 mg singiechain rt-PA given over 6 hours 5 out of 311 (1.6~) patients involved in an American prerandomization pilot trial had intracerebral bleeding (46"). Three of these 5 events occurred within 24 hours of onset of treatment and 3 were fatal during hospitalization. Major hemorrhagic events, defined as either intracerebral hemorrhage or a decline in hemoglobin of ~ 5 g/100 ml, were observed in 41 of these 311 patients (13.2~o). The overall in-hospital mortality in this American series was only 15 of 311 (4.8~). Recent overall experience with single-chain rt-PA at a dose of 80-119 mg was associated with a bleeding incidence of 0.5~o in 406 patients (46r). For this reason the dose ofrt-PA in the American TIMI-II trial was reduced to 100 mg over 6 hours, in harmony with most on-going European trials.

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Chapter 37 M. Verstraete and J. Vermylen

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