Streptokinase-Inducing Hypotension in Acute Myocardial Infarction but Blood Pressure Normalizing in Acute Massive Pulmonary Embolism; Why?

Abstract

Streptokinase is a well-known hypotension inducing agent in acute myocardial infarction. Hypotension is more frequently in inferior myocardial infarction especially if associated with right ventricular dysfunction. On the opposite side, acute massive pulmonary embolism is accompanied by obstructive shock and hypotension. Administration of streptokinase in massive pulmonary embolism dramatically normalizing the blood pressure rather than improving the clinical condition. So, the suggesting hypothesis: streptokinase-inducing hypotension in acute myocardial infarction but blood pressure normalizing in acute massive pulmonary embolism. The research objectives to evaluate this hypothesis might include: Why is streptokinase-inducing hypotension in acute myocardial infarction but normalizing the blood pressure in acute massive pulmonary embolism? The author concluded that streptokinase-inducing hypotension in acute myocardial infarction but blood pressure normalizing in acute massive pulmonary embolism is still obscure.

Keywords: Streptokinase; Hypotension; Acute myocardial infarction; Massive pulmonary embolism; Normalizing the blood pressure

Abbreviations

AMI: Acute Myocardial Infarction; BP: Blood Pressure; C: Complement; PE: Pulmonary Embolism; PESI: Pulmonary Embolism Severity Index Scoring; Plgn: Plasminogen; Pm: Plasmin; RVD: Right Ventricular Dysfunction; SBP: Systolic Blood Pressure; SK: Streptokinase; STEMI: ST-Elevation Myocardial Infarction

Introduction

Streptokinase

Scoping and relevant serial history: Streptokinase (SK) is a thrombolytic medication and enzyme [1]. The drug was listed in the World Health Organization’s (WHO) List of Essential Medicines (EML) as the safest and most effective medicines needed in a health system [2]. Through several years of investigations, Tillett WS. with his student Sherry S, et al. were initially discovered SK in 1933 from beta-hemolytic streptococci species [1,3]. Indeed, Tillett accidentally noticed that streptococci agglutinated in test tubes that contained human plasma but not in those that contained human serum [3]. This was the key step. The prime candidate for this agglutinating activity was fibrinogen. On the other hand, Tillett hypothesized that fibrinogen is adsorbed on the surface of streptococci indicating that the plasma free of fibrinogen. He found that any plasma containing streptococci would not clot, due to lack of free fibrinogen (a key clotting factor) [3]., Garner et al. (27 June 1933) [4] concluded that the presence of fibrinolytic activity of hemolytic streptococci. Sherry S et al. had confirmed using SK as a thrombolytic drug in the management of Acute Myocardial Infarction (AMI) [1]. However, treatment of fibrinous pleural exudates, hemothorax, and tuberculous meningitis was another serendipitous uses [5]. Sherry et al. with his colleges (1958) started using SK in cases of AMI. However, early trials that used SK infusion produced inconsistent results. Indeed, Rentrop et al. and his colleagues (1979) had initiated the intracoronary SK infusion with reperfusion rates that ranging from 70% to 90% in STElevation Myocardial Infarction (STEMI) [5]. Lastly, Gruppo Italiano per la Sperimentazione Della Streptochinasi nell’Infarto Miocardico (GISSI) trial (1986) offered validated SK as an established, effective, and fixed therapy for its use in AMI [1].

Mechanism of action and biological value

Streptokinase is one of the most famous fibrinolytics [6]. Streptokinase composes complexes with human plasminogen can hydrolytically stimulate other unbound plasminogen (Plgn) by activating via bond cleavage to yield Plasmin (Pm). However, three domains to SK, symbolized a (residues 1–150), β (residues 151–287), and γ (residues 288–414). Each domain independently binds Plgn [6]. Plasmin would lyse fibrin that is the main component of blood thrombi, thereby dissolving clots. Extra-synthesis of Pm caused by SK breaking down clots. The ordinary stimulation of Plgn is by proteolysis of the Arg561—Val562 bond [7]. The amino group of Val562 constitutes a salt-bridge with Asp740, which motivates a modulation alteration producing the active protease Pm. When SK is present, it binds to Plgn to form the SK-Plgn complex that converts the substrate Plgn to Pm. Residues 1–59 of SK regulate its capacity to induce an active site inbound Pg by non-proteolytic pathogenesis and to activate substrate Pg in a fibrin-independent manner. Thereafter, complex reposition into an active complex although the Arg561– Val562 bond stays intact. Thus, another residue must replace for the free amino group of Val562 and supply an antagonist for Asp740 in this active complex [8]. Two candidates for this antagonist have been suggested: Ile1 of SK and Lys698 of Plgn. The deletion of Ile1 of SK significantly inhibits its capacity to induce an active site in Plgn, which backups the hypothesis that stabilization of a salt bridge between Ile1 of SK and Asp740 of Plgn is essential for SK to induce an active site in Plgn by a non-proteolytic mechanism [9]. In contrast with the Ile1 substitutions, the Lys698 mutations also diminished the dissociation constant of the SK complex by 15 to 50 fold. These observations suggest that Lys698 is involved in the genesis of the initial SK-Plgn complex [10]. Streptokinase is naturally created by Streptococci spp. bacteria, which use this enzyme to break up blood clots so that they can spread from the initial site of infection. It can also stimulate fibrin [11]. It is similar, in both function and chemistry, but, staphylokinase (Sak) present in Staphylococcus aureus. Staphylokinase is an essential virulence factor [12]. Both enzymes are included in phages [13]. Streptokinase can be used to prevent postoperative adhesions, especially abdominal surgery such as appendectomy, gall stones, and hysterectomy [14].

Streptokinase and hypotension

Determinants of post-SK hypotensive response in STEMI: Hypotension is a common side effect of SK [15]. The most important determinant of hypotension in STEMI patients receiving SK is the rate of drug infusion. However, there is a scarceness of data on the other factors associated with SK-related hypotension [16].

Mechanism of hypotension in STEMI is treated with streptokinase: The possibility of post-SK hypotensive response may be due to a decrease in Peripheral Vascular Resistance (PVR), reflecting a lowering in plasma viscosity caused by the reduction in plasma fibrinogen, a major component of plasma viscosity [18]. This hypothesis was rejected by Gemmil et al. (1993) [15]. They found no association between the fall in fibrinogen, corrected plasma viscosity, and Blood Pressure (BP) response. They also rejected the hypothesis that Fibrin Degradation Products (FDPs) can activate the prostaglandin-prostacyclin system causing vasodilatation and hypotension, as they found no relationship between BP and the fibrin product D-dimer, or changes in fibrinogen [18]. The BP changes posttreatment with SK drug AMI are common but well-tolerated [15]. The mechanism of hypotension is still uncertain but is not related to pastexposure to streptococcal antigen [15]. Whether Complement (C) activation is the cause of transient hypotension during SK infusion in patients with STEMI. The mechanism of hypotension observed post the infusion of SK is not via C-activation, and thus how SK induces hypotension is still unknown?. However, it is a curious finding that some patients develop substantial complement activation and some none at all [17]. Because SK is produced from streptococcal bacteria, it often causes febrile reactions and other allergic problems. It can also cause hypotension that appears to be dose-related [19].

Hypotension in STEMI patients receiving streptokinase has poor prognostic value: It is concluded that although patients with low Systolic Blood Pressure (SBP) during SK infusion have high mortality. So, the level of SBP before the infusion is more mightily accompanied by the outcome [20]. Hypotension is not dependant on pretreatment SK resistance titer, anti-SK IgG concentration, changes in plasma fibrinogen, B-β 15–42 peptide, and D-dimer [15].

Acute massive pulmonary embolism

Scoping and risk stratification classification: Pulmonary Embolism (PE) is a frequent cardiovascular disease and approximately 60-112/100,000 individuals [21]. It is considered the third most common cause of cardiovascular mortality. It is responsible for 100,000-180,000 deaths/year [22,23]. However, PE is usually classified as massive (high-risk), submassive (intermediaterisk), and non-massive (low-risk). It is an initial essential step to evaluate the demanded treatment. Risk stratification scores are also used to assess both morbidity and mortality [24]. Massive PE is defined as suspected or confirmed PE in the presence of shock, sustained hypotension, the absence of a pulse, or persistent profound bradycardia [21,24,25]. In high-risk (massive) PE: there are shock or hypotension (SBP <90 mmHg or decrease in SBP of ≥40 mmHg from baseline) and echocardiographic Right Ventricular Dysfunction (RVD). These patients are about <5% of acute PE patients [26]. The early hospital mortality rate in massive PE patients is ranged between 25% to 65% [27]. Submassive PE is defined as suspected or confirmed PE with RVD in the absence of shock [21,24,25]. Intermediate-risk (submassive) PE: Patients without shock or hypotension but with signs of RVD (non-massive) PE: Patients without shock/hypotension and no signs of RVD or with PESI scoring <1. The early mortality rate in both submassive non-massive PE is below 1% [28].

Thrombolytics guidelines and pulmonary embolism: Indeed, acute PE patients in the absence of shock, hypotension, or signs of RVD are considered to have a low 30-day mortality risk [29]. It should be noted that both the European guidelines (grade 1B) (2014) [25] and the CHEST guidelines (class III, level B) (2016) [30] recommend against the administration of thrombolytics in patients with acute PE in the absence of hypotension. So, thrombolysis with streptokinase is not recommended for these patients [25]. A PESI class of I or II (Table 1) should immediate clinicians to think in outpatient treatment [29,31]. Hemodynamically unstable PE patients are the target for either intravenous thrombolytics or surgical thrombectomy [32]. Thrombolytic medications are acting by transform native Plgn to Pm, which in turn breaks down the fibrin of thromboemboli, causing clot lysis [32]. Streptokinase, urokinase, and alteplase are the only indicated agents for the acute massive PE with hypotension [33-37].

TABLECREATED

Table 1: Pulmonary Embolism Severity Index (PESI) scoring system.

    

    

    Figure 1: Blood pressure configuration post-streptokinase in myocardial infarction and pulmonary embolism.
    

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Citation: Elsayed YMS. Streptokinase-Inducing Hypotension in Acute Myocardial Infarction but Blood Pressure Normalizing in Acute Massive Pulmonary Embolism; Why?. Thromb Haemost Res. 2020; 4(3): 1046.

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